Susceptibility Locus For Schizophrenia Research Articles

Search for schizophrenia susceptibility variants at the HLA-DRB1 locus among a British population

Schizophrenia is a complex mental disorder with unknown aetiology. Both candidate gene and genome-wide association (GWA) studies suggest that the human leukocyte antigen (HLA) system may play a part in development of the illness, but the causal HLA variant(s) remain(s) unclear. Previous studies showed that the DRB1*0101 and DRB1*13 alleles might be associated with a high risk of schizophrenia. Therefore, the present study was undertaken to test their association with the disease by genotyping seven DRB1-tagging single nucleotide polymorphisms (SNPs) in a British population. The results showed that, of the previously reported variants that were associated with schizophrenia, the DRB1*1303 allele was the only one marginally associated with a protective effect on the illness in our sample set (χ² = 4.138, P = 0.042, odds ratio (OR) = 0.42, 95 % confidence interval (CI) 0.27-0.66). Interestingly, a significant association was found for rs424232 (χ² = 9.404, P = 0.002, OR = 0.69, 95 % CI 0.54-0.88), which is a tag SNP for the DRB1*1303 allele and located near to the NOTCH4 gene that is a schizophrenia susceptibility locus confirmed by GWA studies. Analysis with the Haploview program demonstrated that rs424232 was in complete linkage disequilibrium with rs3130297 and rs3131296 present in the NOTCH4 locus. While we have failed to confirm association of the candidate alleles in the DRB1 gene with a high risk of schizophrenia, the present work suggests that the association signal detected in the HLA class II locus may extend a relatively long distance, and more work is needed in order to identify the true causal variants within this region or nearby.

Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at MIR-137

ObjectiveThe Schizophrenia Psychiatric Genome-wide Association (GWAS) Consortium recently reported on five novel schizophrenia susceptibility loci. The most significant finding mapped to a micro-RNA, MIR-137, which may be involved in regulating the function of other schizophrenia and bipolar disorder susceptibility genes. MethodWe genotyped 821 patients with confirmed DSM-IV diagnoses of schizophrenia, bipolar affective disorder I and schizoaffective disorder for the risk SNP (rs1625579) and investigated the clinical profiles of risk allele carriers using a within-case design. We also assessed neurocognitive performance in a subset of cases (n=399) and controls (n=171). ResultsCarriers of the risk allele had lower scores for an OPCRIT-derived positive symptom factor (p=0.04) and lower scores on a lifetime measure of psychosis incongruity (p=0.017). Risk allele carriers also had more cognitive deficits involving episodic memory and attentional control. ConclusionThis is the first evidence that the MIR-137 risk variant may be associated with a specific subgroup of psychosis patients. Although the effect of this single SNP was not clinically relevant, investigation of the impact of carrying multiple risk SNPs in the MIR-137 regulatory network on diagnosis and illness profile may be warranted.

Association study of a new schizophrenia susceptibility locus of 10q24.32–33 in a Han Chinese population

Recently, a new schizophrenia susceptibility locus 10q24.32–q24.33, containing two single-nucleotide polymorphisms (SNPs: rs7914558 and rs11191580), was identified in a genome-wide association study. To examine if this locus is associated with schizophrenia in the Han Chinese population, we analyzed six SNPs, including two SNPs within the region of interest. The sample consisted of 1430 schizophrenia cases and 1570 controls from genetically independent members of the Han population. Single-SNP association, haplotype association and sex-specific association analyses were performed. Three SNPs, rs7914558 (p=1.41×10−4; OR=1.11; 95% CI 1.05–1.17), rs12220375 (p=1.18×10−4; OR=1.06; 95% CI 1.03–1.09) and rs11191580 (p=3.03×10−4; OR=1.05; 95% CI 1.02–1.10), mapped to the locus and were significantly associated in our sample set. Further genotype and haplotype association analyses suggested a similar pattern. Similar to results from European populations, our results provide further evidence that this region associated with schizophrenia in Han Chinese. Results also confirm previous reports suggesting that 10q24.32–q24.33 offers an intriguing new insight into the pathogenesis of schizophrenia and may play an important role in its etiology.

DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population

It is well accepted that schizophrenia has a strong genetic component. Several genome-wide association studies (GWASs) of schizophrenia have been published in recent years; most of them population based with a case-control design. Nevertheless, identifying the specific genetic variants which contribute to susceptibility to the disorder remains a challenging task. A family-based GWAS strategy may be helpful in the identification of schizophrenia susceptibility genes since it is protected against population stratification, enables better accounting for genotyping errors and is more sensitive for identification of rare variants which have a very low frequency in the general population. In this project we implemented a family-based GWAS of schizophrenia in a sample of 107 Jewish-Israeli families. We found one genome-wide significant association in the intron of the DOCK4 gene (rs2074127, p value=1.134×10⁻⁷) and six additional nominally significant association signals with p<1×10⁻⁵. One of the top single nucleotide polymorphisms (p<1×10⁻⁵) which is located in the predicted intron of the CEACAM21 gene was significantly replicated in independent family-based sample of Arab-Israeli origin (rs4803480: p value=0.002; combined p value=9.61×10⁻⁸), surviving correction for multiple testing. Both DOCK4 and CEACAM21 are biologically reasonable candidate genes for schizophrenia although generalizability of the association of DOCK4 with schizophrenia should be investigated in further studies. In addition, gene-wide significant associations were found within three schizophrenia candidate genes: PGBD1, RELN and PRODH, replicating previously reported associations. By application of a family-based strategy to GWAS, our study revealed new schizophrenia susceptibility loci in the Jewish-Israeli population.

Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes

There is genetic evidence that schizophrenia is a polygenic disorder with a large number of loci of small effect on disease susceptibility. Genome-wide association studies (GWASs) of schizophrenia have had limited success, with the best finding at the MHC locus at chromosome 6p. A recent effort of the Psychiatric GWAS consortium (PGC) yielded five novel loci for schizophrenia. In this study, we aim to highlight additional schizophrenia susceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394 schizophrenia cases and 12 462 controls) with expression QTLs (eQTLs) and differential gene expression in whole blood of schizophrenia patients and controls. We examined the 6192 single-nucleotide polymorphisms (SNPs) with significance threshold at P<0.001. eQTLs were calculated for these SNPs in a sample of healthy controls (n=437). The transcripts significantly regulated by the top SNPs from the GWAS meta-analysis were subsequently tested for differential expression in an independent set of schizophrenia cases and controls (n=202). After correction for multiple testing, the eQTL analysis yielded 40 significant cis-acting effects of the SNPs. Seven of these transcripts show differential expression between cases and controls. Of these, the effect of three genes (RNF5, TRIM26 and HLA-DRB3) coincided with the direction expected from meta-analysis findings and were all located within the MHC region. Our results identify new genes of interest and highlight again the involvement of the MHC region in schizophrenia susceptibility.

Genetic Variations in the ADAMTS12 Gene are Associated with Schizophrenia in Puerto Rican Patients of Spanish Descent

ADAMTS12 belongs to the family of metalloproteinases that mediate a communication between specific cell types and play a key role in the regulation of normal tissue development, remodeling, and degradation. Members of this family have been implicated in neurodegenerative and neuroinflammatory, as well as in muscular-skeletal, cardiovascular, respiratory and renal diseases, and cancer. Several metalloproteinases have been associated with schizophrenia. In our previous study of the pedigree from a genetic isolate of Spanish origin in Puerto Rico, we identified a schizophrenia susceptibility locus on chromosome 5p13 containing ADAMTS12. This gene, therefore, is not only a functional but also a positional candidate gene for susceptibility to the disorder. In order to examine possible involvement of ADAMTS12 in schizophrenia, we performed mutation analysis of the coding, 5'- and 3'-untranslated, and putative promoter regions of the gene in affected members of the pedigree and identified 18 sequence variants segregated with schizophrenia. We then tested these variants in 135 unrelated Puerto Rican schizophrenia patients of Spanish origin and 203 controls and identified the intronic variant rs256792 (P = 0.0035; OR = 1.59; 95% CI = 1.16-2.17) and the two-SNP haplotype rs256603-rs256792 (P = 0.0023; OR = 1.62; 95% CI = 1.19-2.21) associated with the disorder. The association remained significant after correction for multiple testing. Our data support the hypothesis that genetic variations in ADAMTS12 influence the risk of schizophrenia.

Demonstration of Uniparental-Isodisomy on Chromosome 22q11.2 in a Patient With Childhood Schizophrenia and Facial Dysmorphology by Whole-Genome Analysis

Back to table of contents Previous article Next article LettersFull AccessDemonstration of Uniparental-Isodisomy on Chromosome 22q11.2 in a Patient With Childhood Schizophrenia and Facial Dysmorphology by Whole-Genome AnalysisOzgur Cogulu, M.D., Erhan Pariltay, M.D., Asude Alpman Durmaz, M.D., Ph.D., Ayca Aykut, M.D., Cumhur Gunduz, Ph.D., Burcu Ozbaran, M.D., Hikmet Hakan Aydin, M.D., Serpil Erermis, M.D., Cahide Aydin, M.D., and Ferda Ozkinay, M.D.Ozgur CoguluSearch for more papers by this author, M.D., Erhan PariltaySearch for more papers by this author, M.D., Asude Alpman DurmazSearch for more papers by this author, M.D., Ph.D., Ayca AykutSearch for more papers by this author, M.D., Cumhur GunduzSearch for more papers by this author, Ph.D., Burcu OzbaranSearch for more papers by this author, M.D., Hikmet Hakan AydinSearch for more papers by this author, M.D., Serpil ErermisSearch for more papers by this author, M.D., Cahide AydinSearch for more papers by this author, M.D., and Ferda OzkinaySearch for more papers by this author, M.D.Published Online:1 Jan 2012https://doi.org/10.1176/appi.neuropsych.11010027AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Chromosome 22q11 and the gene/genes in this region that may be responsible for susceptibility to schizophrenia have been previously studied.1 We present a novel finding in schizophrenia that is a maternally-inherited uniparental disomy (UPD) on chromosome 22 cent-q11.2 in a female patient with disorganized behavior and psychotic symptoms.Case ReportAn 8-year-old girl was referred because of mental retardation and behavioral problems. Written, informed consent was obtained from the parents for the publication of the patient's details.She was born to consanguineous parents at 31–32 weeks' gestation. Her birth percentiles were in normal ranges. Her developmental milestones were slightly delayed. There was no history of psychiatric disorder in the relatives except that there were two members with idiopathic mental retardation. Her physical assessment at age 8 revealed elfin-like facial features, sparse medial eyebrows, arched eyebrows, hypertelorism, depressed nasal bridge, bulbous nasal tip, downturned corners of mouth, thick lower lip, and joint laxity. Imaging studies were normal.Psychiatric evaluation at age 3 revealed language-development delay, restricted social relationships, echolalia, and lack of interest in peer-relationships and toys. Her psychometric evaluation with developmental tests showed a 1-year delay.2 Echolalia, social-relationship restrictions, and not having imaginary play were noted as autistic-like features. At age 6, unrealistic fears, psychomotor agitation, disorganized behavior, auditory and visual hallucinations, incoherence, irrelevant and disorganized speech, and delusions were observed. She was diagnosed as “very-early-onset schizophrenia” according to the DSM-IV criteria.3 Her Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) scores were 75 and 72, respectively. Her psychiatric disorder severity score was 6, according to Clinic Global Impression Scale–Severity (CGIS–S).Her karyotype and FISH analysis were normal. Whole-genome analysis by Affymetrix Human SNP Assay 6.0 kit revealed inherited copy-number variations (CNVs) and loss-of-heterozygosity (LOH) on a number of regions, which could be due to the parental consanguinity. LOH on chromosome 22 cent-q11.2 spanned 6 Mb. CNV analysis showed no evidence of any deletion in this region. The same analysis for the parents was normal. Microsatellite marker analysis with 8 markers confirmed maternally-inherited UPD (Figure 1). Catechol-O-methyltransferase (COMT) gene at 22q11, which has been identified as a susceptibility locus for schizophrenia, revealed 100-fold down-regulation, as compared with a control group. Therefore, it could be speculated that COMT could be one of a number of other genes down-regulated in this UPD region that may have contributed to the clinical presentation.FIGURE 1. Microsatellite Marker Analysis of the Family (microsatellite markers in the UPD region are highlighted in gray)In conclusion, this is the first report reinforcing the link between 22q11 and schizophrenia with two novel findings; first, down-regulation of COMT expression, which may be due to the maternally-inherited UPD; and second, phenotypic effects of the same abnormality.Ege UniversityMedical FacultyDept. of Pediatrics (OC,AA,FO)Medical Genetics (EP,AAD)Medical Biology (CG)Child Psychiatry (BO,SE,CA)Medical Biochemistry (HHA)Izmir, TurkeyCorrespondence: Asude Alpman Durmaz Ege University, Faculty of Medicine, Department of Medical Genetics; e-mail: [email protected]com Asude Alpman DurmazCompeting Interests: None

AS23-01 - Travelling with high-speed through the forest of schizophrenia genetics: from GWAS to biology

Genome-wide association studies (GWAS) have been successful in identifying replicable susceptibility loci for schizophrenia. The most replicated GWAS association is at chromosome 6p (MHC). However, identifying the causal gene networks, the specific genes, and functional variants has proven difficult for schizophrenia, just like for most other complex disorders. Since almost all GWAS associated SNPs are either intergenic or intragenic but uncorrelated with obvious candidate functional variation such as missense or nonsense SNPs, it is likely that gene regulation is involved in schizophrenia susceptibility. This suggests that an integrative systems biology approach, one that combines DNA sequence and structural information with functional data, will be useful to study the biological mechanisms underlying the GWAS statistical associations and to identify new disease genes. To this end, we are investigating the genetic etiology of SZ by generating transcriptional profiles under conditions designed to reveal biological mechanisms involved in conferring risk, for example, by using environmental perturbations of etiological and pharmacological relevance on simple cellular models. This strategy, by refocusing transcriptional activity towards targets of specific environmental perturbations, is also useful for testing specific hypotheses of schizophrenia pathophysiology independently of GWAS results. I will be presenting transcriptional profiles at baseline that show association with schizophrenia, and the results of applying a number of external stimuli.

P-1328 - Genome-wide association analysis with brain structure measures as a quantitative phenotype for first-episode schizophrenia

Objective Schizophrenia (SZ) is a syndrome, which is the most common form with paranoid delusions and auditory hallucinations late in early adulthood or in adolescence, and the changed structure of hippocampus, thalamus, amygdale region. Combined imaging with genetics data, we want to obtain genetic susceptibility loci for SZ. Method Imaging and genetics data which were obtained from the Mental Health Centre of the West China Hospital. In our study, we applied a genome-wide study of the change structure of brain regions. Results We indentified three genes or chromosomal region through having at least 2 single-nucleotide polymorphisms (SNPs) each significant at P −5 for the interaction/main effect model (TBXAS1, PIK3C2G, and IL17A-IL17F). Conclusion The genome-wide association study identifies three genes or chromosomal regions, which are related with the volume of hOC3v_V3v_Left hemisphere, Lobule_X_Vermis_Left hemisphere, Lobule_X_Vermis_Right hemisphere and maybe as a risk factor for schizophrenia. This result highlight the usefulness of endophenotype for neuropsychiatric diseases. But these findings are conformed through independent replication studies in future.

Comprehensive Gene-Based Association Study of a Chromosome 20 Linked Region Implicates Novel Risk Loci for Depressive Symptoms in Psychotic Illness

BackgroundPrior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants.MethodsWe analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold-truncated product of P-values for each locus.ResultsWhile no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (P emp<2×10−5) based on the minimum P-value and truncated-product methods, respectively.ConclusionsUsing a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci.

Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2

To identify susceptibility loci for schizophrenia, we performed a two-stage genome-wide association study (GWAS) of schizophrenia in the Han Chinese population (GWAS: 746 individuals with schizophrenia and 1,599 healthy controls; validation: 4,027 individuals with schizophrenia and 5,603 healthy controls). We identified two susceptibility loci for schizophrenia at 6p21-p22.1 (rs1233710 in an intron of ZKSCAN4, P(combined) = 4.76 × 10(-11), odds ratio (OR) = 0.79; rs1635 in an exon of NKAPL, P(combined) = 6.91 × 10(-12), OR = 0.78; rs2142731 in an intron of PGBD1, P(combined) = 5.14 × 10(-10), OR = 0.79) and 11p11.2 (rs11038167 near the 5' UTR of TSPAN18, P(combined) = 1.09 × 10(-11), OR = 1.29; rs11038172, P(combined) = 7.21 × 10(-10), OR = 1.25; rs835784, P(combined) = 2.73 × 10(-11), OR = 1.27). These results add to previous evidence of susceptibility loci for schizophrenia at 6p21-p22.1 in the Han Chinese population. We found that NKAPL and ZKSCAN4 were expressed in postnatal day 0 (P0) mouse brain. These findings may lead to new insights into the pathogenesis of schizophrenia.

Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems

PurposeRecently, molecular cytogenetic techniques have identified novel copy number variants in individuals with schizophrenia. However, no large-scale prospective studies have been performed to characterize the broader spectrum of phenotypes associated with such copy number variants in individuals with unexplained physical and intellectual disabilities encountered in a diagnostic setting. MethodsWe analyzed 38,779 individuals referred to our diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. We also analyzed the indications for study for individuals with copy number variants overlapping those found in six individuals referred for schizophrenia. ResultsAfter excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), we identified 1113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the six individuals referred to our laboratory for schizophrenia. Of these, 1035 had a copy number variant of one of six recurrent loci: 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11, and 22q11.2. The indications for study for these 1150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. ConclusionThe results from our study, the largest genotype-first analysis of schizophrenia susceptibility loci to date, suggest that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and imply the existence of shared biologic pathways among multiple neurodevelopmental conditions.

The effect of genome-wide supported variants in CACNA1C and NRGN on functional correlates of episodic memory encoding and retrieval

Objective: Genetic studies implicated variation in NRGN and CACNA1C as a susceptibility locus for bipolar disorder, schizophrenia and major depression. Method: We investigated the influence of the CACNA1C single nucleotide polymorphism (SNP) rs1006737 and rs12807809 of NRGN on functional correlates of episodic memory encoding and retrieval. Brain activation was measured with functional magnetic resonance imaging (fMRI) during an episodic memory encoding and retrieval task in 94 healthy individuals who were genotyped for both variants. Results: In the fMRI experiment, while there were no differences in behavioral performance, neural activation-mainly in the superior frontal gyrus and inferior and middle temporal gyrus – was associated with CACNA1C genotype during encoding and retrieval. For NRGN, differential brain activation was evident in the anterior cingulate cortex for the encoding and posterior cingulate regions during retrieval. Conclusions: Our data suggest that both variants influence the neural systems related to memory processes: Brain activations during encoding and retrieval of new material might compensate for otherwise insufficient performance. These findings are in line with results of imaging studies in affective disorder and schizophrenia. It may explain some of the brain activation variation found in these disorders and healthy subjects.

Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family‐based, Arab‐Israeli sample

While the use of population-based samples is a common strategy in genome-wide association studies (GWASs), family-based samples have considerable advantages, such as robustness against population stratification and false-positive associations, better quality control, and the possibility to check for both linkage and association. In a genome-wide linkage study of schizophrenia in Arab-Israeli families with multiple affected individuals, we previously reported significant evidence for a susceptibility locus at chromosome 6q23.2-q24.1 and suggestive evidence at chromosomes 10q22.3-26.3, 2q36.1-37.3 and 7p21.1-22.3. To identify schizophrenia susceptibility genes, we applied a family-based GWAS strategy in an enlarged, ethnically homogeneous, Arab-Israeli family sample. We performed genome-wide single nucleotide polymorphism (SNP) genotyping and single SNP transmission disequilibrium test association analysis and found genome-wide significant association (best value of P=1.22×10(-11)) for 8 SNPs within or near highly reasonable functional candidate genes for schizophrenia. Of particular interest are a group of SNPs within and flanking the transcriptional factor LRRFIP1 gene. To determine replicability of the significant associations beyond the Arab-Israeli population, we studied the association of the significant SNPs in a German case-control validation sample and found replication of associations near the UGT1 subfamily and EFHD1 genes. Applying an exploratory homozygosity mapping approach as a complementary strategy to identify schizophrenia susceptibility genes in our Arab Israeli sample, we identified 8 putative disease loci. Overall, this GWAS, which emphasizes the important contribution of family based studies, identifies promising candidate genes for schizophrenia.

OPCML Gene as a Schizophrenia Susceptibility Locus in Thai Population

Opioid-binding protein/cell adhesion molecule (OPCML) gene has been recently identified as a susceptibility gene for schizophrenia in Europeans. This study aims to investigate the association between single nucleotide polymorphisms (SNPs) in the OPCML gene and risk of schizophrenia in a Thai population. DNA samples of 115 schizophrenia patients and 173 normal controls were genotyped using high-resolution melting analysis and analyzed by chi-square test of SPSS software. We observed a strong association between an intronic SNP of the OPCML gene (rs1784519) and the risk of schizophrenia in the Thai population [P = 0.00036; odds ratio for the minor A allele, 2.11(1.57-2.84)]. The previously discovered SNP associated with schizophrenia in Europeans, rs3016384, also showed significant association with schizophrenia in the Thai population [P = 0.01; odds ratio of the minor T allele, 0.59 (0.44-0.79)]. Therefore, the OPCML gene is considered to be a schizophrenia-susceptible gene in the Thai population.

No association between the PCM1 gene and schizophrenia: A multi-center case-control study and a meta-analysis

Alterations in centrosomal function have been suggested in the pathology of schizophrenia. The molecule pericentriolar material 1 (PCM1) is involved in maintaining centrosome integrity and in the regulation of the microtubule cytoskeleton. PCM1 forms a complex at the centrosome with the disrupted-in-schizophrenia 1 (DISC1) protein, which is a major susceptibility factor for schizophrenia. The association between genetic variants in the PCM1 gene and schizophrenia has been reported by several case-control studies, linkage studies and a meta-analysis. The aims of this study are to replicate the association between four single-nucleotide polymorphisms (SNPs) in the PCM1 gene and schizophrenia in a Japanese population (1496 cases and 1845 controls) and to perform a meta-analysis of the combined sample groups (3289 cases and 3567 controls). We failed to find a significant association between SNPs or haplotypes of the PCM1 gene and schizophrenia in the Japanese population ( P > 0.28). The meta-analysis did not reveal an association between the four examined SNPs and schizophrenia. Our data did not support genetic variants in the PCM1 gene as a susceptibility locus for schizophrenia.

Study of HLA Class I gene in Indian schizophrenic patients of Siliguri, West Bengal

The authors studied the prevalence of the human leukocyte antigen (HLA) Class I gene in 136 (85 male, 51 female) India-born schizophrenia patients residing in and around the Siliguri subdivision of West Bengal by the PCR-SSP method. The control group consisted of 150 age- and sex-matched healthy individuals from the same ethnic group as the patients. Increased frequency of HLA A*03 as well as decreased frequencies of HLA A*31 and HLA B*51, was noted. The study suggests the possible existence of a susceptibility locus for schizophrenia within the HLA region.

No NRG1 V266L in Chinese patients with schizophrenia

NRG1 is one of the best-supported schizophrenia (SZ) susceptibility genes. A NRG1 V266L missense mutation has been found to be associated with SZ in several populations. V266L is not in linkage disequilibrium with any of the SZ-associated NRG1 haplotypes described thus far, and may represent an independent SZ susceptibility locus within NRG1 gene. V266 is a highly conserved residue and its substitution is predicted to have a deleterious effect on the protein. As there are no data for V266L in Chinese, and given the potential relevance of this mutation, we investigated the V266L prevalence in 270 Chinese patients with schizophrenia and 270 ethnically matched controls. V266L was found neither in patients nor in controls. Lack of replication of an association across populations may be because of the differences in linkage disequilibrium structure or allele frequencies. Some true associations may not be replicated regardless of the sample size of the study.

Linkage and association on 8p21.2-p21.1 in schizophrenia

In the past decade, we and others have consistently reported linkage to a schizophrenia (SZ) susceptibility region on chromosome 8p21. Most recently, in the largest SZ linkage sample to date, a multi-site international collaboration performed a SNP-based linkage scan (~6,000 SNPs; 831 pedigrees; 121 from Johns Hopkins (JHU)), that showed the strongest evidence for linkage in a 1 Mb region of chr 8p21 from rs1561817 to rs9797 (Z(max) = 3.22, P = 0.0004) [Holmans et al. 2009. Mol Psychiatry]. We have investigated this 8p21 peak region further in two ways: first by linkage and family-based association in 106 8p-linked European-Caucasian (EUC) JHU pedigrees using 1,402 SNPs across a 4.4 Mb region surrounding the peak; second, by an independent case-control association study in the genetically more homogeneous Ashkenazim (AJ) (709 cases, 1,547 controls) using 970 SNPs in a further narrowed 2.8 Mb region. Family-based association analyses in EUC pedigrees and case-control analyses in AJ samples reveal significant associations for SNPs in and around DPYSL2 and ADRA1A, candidate genes previously associated with SZ in our work and others. Further, several independent gene expression studies have shown that DPYSL2 is differentially expressed in SZ brains [Beasley et al. 2006. Proteomics 6(11):3414–3425; Edgar et al. 2000. Mol Psychiatry 5(1):85–90; Johnston-Wilson et al. 2000. Mol Psychiatry 5(2):142–149] or in response to psychosis-inducing pharmaceuticals [Iwazaki et al. 2007. Proteomics 7(7):1131–1139; Paulson et al. 2004. Proteomics 4(3):819–825]. Taken together, this work further supports DPYSL2 and the surrounding genomic region as a susceptibility locus for SZ.

Most genome-wide significant susceptibility loci for schizophrenia and bipolar disorder reported to date cross-traditional diagnostic boundaries

Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10(-5)). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects.