Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto‐hippocampal connectivity

Background: Genome‐wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto‐hippocampal connectivity. Methods: We used functional magnetic resonance imaging to measure neural activation during an n‐back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working‐memory‐related DLPFC activation and functional integration using a seed region functional connectivity approach. Results: Rs1006737 genotype was associated with altered right‐hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G‐allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto‐hippocampal connectivity with rs1006737 A alleles. Conclusions: We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype‐related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder. Hum Brain Mapp 35:1190–1200, 2014. © 2013 Wiley Periodicals, Inc.     

MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese

Recently, evidence has accumulated indicating that the MIR137 gene and the target gene CACNA1C of miR-137 might be two of the most robustly implicated genes in schizophrenia. In this study, we examined 33 single nucleotide polymorphisms (SNPs) located in two genes by performing an association analysis in a cohort of 1430 schizophrenia patients and 1570 healthy Han Chinese control subjects. Single SNP association, sex-specific association and haplotype association analyses were performed. For the rs1625579 marker in MIR137 and the rs1006737 and rs4765905 markers in CACNA1C, significant differences in the allele frequencies were found between the patients and controls (p = 0.007949, p = 0.013658 and p = 0.013999, respectively), and the genotype association analysis for them suggested a similar pattern (p = 0.023167, p = 0.046623 and p = 0.047824, respectively). Further analysis of the haplotype rs1006737–rs4765905–rs882194 in CACNA1C showed significant associations with schizophrenia (corrected global p < 0.005), and two haplotypes (ACC and ACT) in the block were significantly increased in the patients. When the samples were analyzed separately by gender, we found no significant sex-specific associations in MIR137 and CACNA1C, which was similar to the results from the relevant haplotype association analysis in the female and male subgroups. We have provided new evidence supporting the association between MIR137 and CACNA1C and schizophrenia in the Han Chinese population.     

Evidence for cis‐acting regulation of ANK3 and CACNA1C gene expression

Quinn EM, Hill M, Anney R, Gill M, Corvin AP, Morris DW. Evidence for cis‐acting regulation of ANK3 and CACNA1C gene expression.
Bipolar Disord 2010: 12: 440–445. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Genome‐wide association studies (GWAS) have identified Ankyrin‐G (ANK3) and the α‐1C subunit of the L‐type voltage‐gated calcium channel (CACNA1C) as susceptibility genes for bipolar disorder. Available biological information on these genes suggests a potential molecular mechanism involving ion channel dysfunction. The associated single nucleotide polymorphisms (SNPs) at ANK3 (rs10994336) and CACNA1C (rs1006737) are both intronic with no obvious impact on gene function. We investigated whether, instead of affecting protein function, these risk variants might impact on gene regulation affecting expression. Methods: We have done this by testing for allelic expression imbalance (AEI) to identify cis‐acting regulatory polymorphisms. Results: We identified evidence of cis‐acting variation at both loci in HapMap Caucasian Europeans from Utah (CEU) lymphoblastoid cell lines. There was considerable evidence of AEI at ANK3 with more than half of all heterozygous samples (21 out of 34) for marker SNP rs3750800 showing AEI and a small number of samples showing near monoallelic expression. The AEI at either gene could not be attributed to the GWAS‐associated SNPs. Conclusions: These data indicate that there is genetic variation local to both genes affecting their expression, but that this variation is not responsible for increasing risk of bipolar disorder.     

The effects of CACNA1C gene polymorphism on spatial working memory in both healthy controls and patients with schizophrenia or bipolar disorder

CACNA1C gene polymorphism (rs1006737) is a susceptibility factor for both schizophrenia (SCZ) and bipolar disorder (BP). However, its role in working memory, a cognitive function that is impaired in both diseases, is not clear. Using three samples, including healthy controls, patients with SCZ, and patients currently in manic episodes of BP, this study tested the association between the SNP rs1006737 and spatial working memory as measured by an N-back task and a dot pattern expectancy (DPX) task. Among SCZ patients and healthy controls, the clinical risk allele was associated with impaired working memory, but the association was either in opposite direction or non-significant in patients with BP. These results indicated that rs1006737 may have differential effects on working memory in different disease populations and pointed to the necessity for more studies in different patient populations.     

Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding

Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel Ca_V1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the ‘missing heritability'' of complex phenotypes.     

Association study in a Sardinian sample between bipolar disorder and the nuclear receptor REV‐ERBα gene,a critical component of the circadian clock system

Objective: The aim of our study was to investigate the association between REV‐ERBα gene (NR1D1) single nucleotide polymorphisms (SNPs) and bipolar disorder (BP) in a case‐control sample of Sardinian ancestry and evaluate its effect on age at onset (AAO) of BP. Methods: We genotyped SNPs rs12941497 (SNP1) and rs939347 (SNP2), located, respectively, in the first intron and in the 5′UTR region of the gene, in a sample comprised of 300 bipolar patients and 300 healthy controls of Sardinian ancestry. We also studied AAO by means of admixture analysis, obtaining a cutoff point of age 22 and then carrying out association analysis between the two AAO groups. Results: In the case‐control comparison, single marker analysis showed no association for any of the SNPs tested. Haplotype analysis showed a nominally significant association for two haplotypes of SNPs 1‐2. Comparing the early‐ and later‐onset groups, nominal association was found for SNP1. Haplotype analysis showed that one haplotype was nominally associated with the later‐onset group. Conclusions: Our results, indicating a nominal association of the REV‐ERBα gene with BP, suggest a possible role of REV‐ERBα in the pathogenesis of BP. Further investigation of larger independent samples and different populations is warranted.     

CACNA1C SNP rs1006737 associates with bipolar I disorder independent of the Bcl-2 SNP rs956572 variant and its associated effect on intracellular calcium homeostasis

Objectives. Intracellular calcium (Ca²⁺) dyshomeostasis (ICDH) has been implicated in bipolar disorder (BD) pathophysiology. We previously showed that SNP rs956572 in the B-cell CLL/lymphoma 2 (Bcl-2) gene associates with elevated B lymphoblast (BLCL) intracellular Ca²⁺ concentrations ([Ca²⁺]_B) differentially in BD-I. Genome-wide association studies strongly support the association between BD and the SNP rs1006737, located within the L-type voltage-dependent Ca²⁺ channel α1C subunit gene (CACNA1C). Here we investigated whether this CACNA1C variant also associates with ICDH and interacts with SNP rs956572 on [Ca²⁺]_B in BD-I. Methods. CACNA1C SNP rs1006737 was genotyped in 150 BD-I, 65 BD-II, 30 major depressive disorder patients, and 70 healthy subjects with available BLCL [Ca²⁺]_B and Bcl-2 SNP rs956572 genotype measures. Results. SNP rs1006737 was significantly associated with BD-I. The [Ca²⁺]_B was significantly higher in BD-I rs1006737 A compared with healthy A allele carriers and also in healthy GG compared with A allele carriers. There was no significant interaction between SNP rs1006737 and SNP rs956572 on [Ca²⁺]_B. Conclusions. Our study further supports the association of SNP rs1006737 with BD-I and suggests that CACNA1C SNP rs1006737 and Bcl-2 SNP rs956572, or specific causal variants in LD with these proxies, act independently to increase risk and ICDH in BD-I.     

CACNA1C polymorphism and brain cortical structure in bipolar disorder

BackgroundThe CACNA1C gene encodes the 1C subunit of L-type voltage-gated calcium channels and has been associated with several psychiatric syndromes — including bipolar disorder — in many genome-wide association studies. Experimental and clinical studies have reported changes with respect to behaviour and biomarkers in risk allele carriers, corroborating the essential role of the CACNA1C gene in neurons, during development and in the mature brain. However, the association of this gene with regional cortical thickness has not been evaluated in patients with bipolar disorder.MethodsUsing magnetic resonance imaging, we measured the average cortical thickness of 68 brain regions in 87 patients genotyped for the single-nucleotide polymorphism rs1006737 in CACNA1C.ResultsWe found associations with the mean thickness of several cortical areas: the left lateral orbitofrontal and rostral anterior cingulate cortices, as well as other parts of the frontal and parietal cortices.Limitations: This cross-sectional cohort study could not fully differentiate correlation from causation.ConclusionThe CACNA1C polymorphism rs1006737 is associated with the mean thickness of cortical brain areas that have been shown to be altered in bipolar disorder.     

Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1?M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.     

A genome-wide supported variant in CACNA1C influences hippocampal activation during episodic memory encoding and retrieval

The alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene is one of the best replicated susceptibility loci for bipolar disorder, schizophrenia and major depression. It is involved in learning, memory and brain plasticity. Genetic studies using functional magnetic resonance imaging (fMRI) reported evidence of association with the CACNA1C single nucleotide polymorphism rs1006737 with functional correlates of episodic memory encoding and retrieval, especially activations in the hippocampus. These results, however, are inconsistent with regard to the magnitude and directionality of effect. In the present study, brain activation was measured with fMRI during an episodic memory encoding and retrieval task using neutral faces in two independent samples of 94 and 111 healthy subjects, respectively. Within whole brain analyses, a main effect of genotype emerged mainly in the right hippocampus during encoding as well as retrieval within the first sample: Carriers of the minor allele (A) exhibited lower activations compared to G/G allele carriers. This effect could be replicated within the second sample, however, only for the retrieval condition. The results strengthen findings that rs1006737 is associated with neural systems related to memory processes in hippocampal regions which are detectable in healthy subjects.     

Initial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder

Background

The polymorphism rs1006737 within the CACNA1C gene is associated with increased risk for bipolar disorder (BD) and variations in brain morphology and function of subcortical regions. Here we sought to investigate the influence of CACNA1C polymorphism on key subcortical brain structures implicated in the pathophysiology of BD.

Methods

Structural magnetic resonance imaging scans were acquired from 41 euthymic patients with BD and 40 healthy controls, who were also genotyped for the CACNA1C rs1006737 polymorphism. The effect of diagnosis, genotype and their interaction was examined in predefined volumes of interest in the basal ganglia, hypothalamus and amygdala extracted using SPM5.

Results

Carriers of the CACNA1C rs1006737 risk allele showed increased grey matter density in the right amygdala and right hypothalamus irrespective of diagnosis. An interaction between genotype and diagnosis was observed in the left putamen which was smaller in BD patients carrying the risk allele than in healthy controls.

Conclusions

: The CACNA1C rs1006737 polymorphism influences anatomical variation within subcortical regions involved in emotional processing.     

Family-based association studies of the TCP1 gene and schizophrenia in the Chinese Han population

Summary. A previous case-control study by Yang et al. indicated that the TCP1 gene in 6q25 was associated with schizophrenia in the Han population. To replicate this result, we selected eight SNPs (rs2273828, rs3818298, rs1547094, rs1547093, rs2295898, rs2295899, rs4832, rs15982) spanning the whole gene and performed a family-based study using 325 trios samples. Our transmission disequilibrium test showed neither allele nor haplotype association with schizophrenia, and suggests that the TCP1 locus is not associated with schizophrenia in the Chinese population. Since 6q25 has consistently been found to be a susceptible region for schizophrenia, we suggest that other genes within this region should be the focus of attention. The first and second authors contributed equally to this work     

The NADH‐ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism

Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Jinde S, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N. The NADH‐ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism. Objective: Autism appears to have a strong genetic component. The product of the NADH‐ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene is included in the mitochondrial electron transport chain. Method: We performed a case–control study of 235 patients with autism and 214 controls and examined three single‐nucleotide polymorphisms (SNPs) within this gene in a Japanese population. We then conducted a transmission disequilibrium test (TDT) analysis in 148 autistic trios. Results: In the case–control study, two SNPs (rs12666974 and rs3779262) showed a significant association with autism (P = 0.00064 and 0.00046 respectively). Furthermore, a haplotype containing these two SNPs showed a significant association (P‐global = 0.0013, individual haplotype A‐A : P = 0.010). In TDT analysis, the global and A‐A haplotype P‐values also indicated significant associations. Minor allele and genotype frequencies were decreased in the autistic subjects. Conclusion: We found significant association between the NDFA5 gene and autism.     

ANK3 and CACNA1C--missing genetic link for bipolar disorder and major depressive disorder in two German case-control samples

Recent genome-wide association studies (GWAS) and metaanalyses revealed genetic associations for ANK3 (ankyrin 3) and CACNA1C (alpha 1C subunit of the L-type voltage gated calcium channel) with bipolar disorder (BPD). Several findings from clinical, epidemiological, and genetic studies point towards a common biological background of BPD and major depressive disorder (MDD). We were interested whether this also applies for ANK3 and CACNA1C and tested associations of single nucleotide polymorphisms (SNPs) in these genes with MDD in two Caucasian case-control samples. Sample 1 (Munich Antidepressant Response Signature Project/MARS – MDD) consisted of 720 depressed inpatients and 542 psychiatric healthy controls. Sample 2 (unipolar recurrent depression (URD)) consisted of 827 patients with URD and 860 psychiatric healthy controls. After stringent quality control we analyzed 262 SNPs (sample 1) and 504 SNPs (sample 2) and imputed further 5771 SNPs (sample 1) and 5534 SNPs (sample 2) from Hapmap Phase 2 data in the ANK3 and CACNA1C gene regions. Additionally, a metaanalysis of both samples was performed. Several SNPs in both genes were nominally associated with MDD with the highest association in the 3′-region of ANK3 (rs10994143, nominal p = 3.3*10^?4) in the metaanalysis of both samples. None of these results remained significant after correction for multiple testing. No association of MDD with SNPs previously reported in BPD studies could be detected. By analyzing the LD-structure, our highest associated SNPs could not be linked to the SNPs previously reported in BPD. Regarding ANK3 and CACNA1C, our findings do not support a strong genetic link between BPD and MDD for these two genes.     

Dysbindin gene (<Emphasis Type="Italic">DTNBP1</Emphasis>) and schizophrenia in Korean population

Dysbindin gene (DTNBP1) has been consistently reported to be associated with schizophrenia. However data from East Asian population has been sparse and inconsistent till today. This study tried to replicate the genetic association of DTNBP1 with schizophrenia in a large Korean sample, as well as analyzing the association of DTNBP1 with clinical variables. Nine hundred and eight (908) patients with schizophrenia and 601 controls were investigated. The high-throughput genotyping method using pyrosequencer (Biotage AB, Sweden) was used for genotyping 4 SNPs (rs3213207, rs1011313, rs760761, and rs2619522). Haplotype analyses revealed a significant association with schizophrenia (P < 0.0001) with the haplotypes A-C-C-C and A-C-T-A having an eminent protective effect toward schizophrenia. The major contribution to the difference in the haplotype distribution between patients and the controls was the rs760761 (C/T) and rs2619522 (A/C) haplotypes (P < 0.0001). No association of DTNBP1 with other clinical variables was found. In conclusion, the present study suggests a possible protective effect of rare DTNBP1 variants in schizophrenia, although subsequent studies in different ethnic groups are warranted.     

Further evidence for genetic association of CACNA1C and schizophrenia: New risk loci in a Han Chinese population and a meta-analysis

CACNA1C (12p13.3) has been implicated as a susceptibility gene for schizophrenia by several replicated genome wide association studies. While these results have been consistent among studies in European populations, the findings in East Asian populations have varied. To test whether CACNA1C is a risk gene for schizophrenia, we conducted a case–control study in 5897 schizophrenic patients and 6323 healthy control subjects selected from Han Chinese population. Our study replicated the positive associations of rs1006737 (P = 0.0108, OR = 1.16, 95% CI: 1.03–1.29) and rs1024582 (P = 0.0062, OR = 1.18, 95% CI: 1.05–1.33), and identified a novel risk locus, rs2007044 (P = 0.0053, OR = 1.08, 95% CI: 1.02–1.14). A meta-analysis of rs1006737 combining our study and previous studies was conducted in a total of 8222 schizophrenia cases and 24,661 healthy controls. In the meta-analysis, the association between rs1006737 and schizophrenia remained significant (OR = 1.14, 95% CI: 1.07–1.22, P = 0.0001). Stratified analysis showed no heterogeneity between East Asian and European ancestries (χ²[1] = 0.07, P = 0.795), and the difference in pooled ORs between ancestries was not significant (Z = 0.25, P = 0.801). Our results provide further support for associations of rs1006737 and rs1024582 with schizophrenia, identify a new risk locus rs2007044 in a Han Chinese population, and further establish CACNA1C as an important susceptibility gene for the disease across world populations.     

Serotonin 1A receptor gene,schizophrenia and bipolar disorder: An association study and meta-analysis

Several investigations have reported associations between serotonin 1A (5-HT1A) receptor and major psychiatric disorders, such as schizophrenia and bipolar disorder (BP), making the 5-HT1A receptor gene (HTR1A) a good candidate gene for the pathophysiology of schizophrenia and BP. To evaluate the association between HTR1A and schizophrenia and BP, we conducted a case-control study of Japanese population samples with two single- nucleotide polymorphisms (SNPs), including rs6295 (C-1019G) in HTR1A. In addition, we conducted a meta-analysis of rs6295, which has been examined in other studies. Using one functional single- nucleotide polymorphism (SNP; rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (857 schizophrenic patients, 1028 BP patients and 1810 controls) in the Japanese population. Two association studies for schizophrenia and three association studies for BP, including this study, met our criteria for the meta-analysis of rs6295. We found an association between HTR1A and Japanese BP in a haplotype-wise analysis, the significance of which remained after Bonferroni correction. In addition, we detected an association between rs6295 and BP in the meta-analysis (fixed model: P(Z) = 0.000400). However, we did not detect an association between HTR1A and schizophrenia in the allele/genotype-wise, haplotype-wise or meta-analysis. HTR1A may play an important role in the pathophysiology of BP, but not schizophrenia in the Japanese population. In the meta-analysis, rs6295 in HTR1A was associated with BP patients.     

Extreme population differences across Neuregulin 1 gene, with implications for association studies

Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F(ST) values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.     

Identifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations

The dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP 'A') in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia.