Schizophrenia Loci Research Articles

No associations exist between five functional polymorphisms in the catechol-O-methyltransferase gene and schizophrenia in a Japanese population

Catechol- O-methyltransferase (COMT) is one of the enzymes that degrade catecholamine neurotransmitters including dopamine. The COMT gene is located on 22q11.2, a common susceptibility locus for schizophrenia. Therefore, COMT is a strong functional and positional candidate gene for schizophrenia. A common functional polymorphism (rs4680, Val158Met) has been extensively tested for an association with schizophrenia, but with conflicting results. Recent studies indicate that if COMT is implicated in susceptibility to schizophrenia, this cannot be wholly accounted for by the Val158Met polymorphism. To assess this view, the authors conducted a case–control association study (399 patients with schizophrenia and 440 control subjects) for five functional polymorphisms (rs2075507, rs737865, rs6267, rs4680 and rs165599) in Japanese subjects. There were no significant associations found between the polymorphisms or haplotypes of COMT and schizophrenia. The present study shows that these five functional COMT polymorphisms do not play a major role in conferring susceptibility to schizophrenia in Japanese.

Crystal structure of human myo‐inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures

The human IMPA2 gene, which encodes myo-inositol monophosphatase 2 (IMPA2), is mapped onto 18p11.2, a susceptibility region for bipolar disorder. This chromosomal region has also been proposed to include a susceptibility locus for schizophrenia and febrile seizures. Here we report the crystal structures of human IMPA2 and its complex with calcium and phosphate ions. Human IMPA2 comprises an alpha-beta protein with a five-layered sandwich of alpha-helices and beta-sheets (alpha-beta-alpha-beta-alpha). The crystal structure and analytical ultracentrifugation results indicated that IMPA2 exists as a dimer in solution. The overall structure of IMPA2 is similar to that of IMPA1, except for the loop regions. In IMPA1, the loop region (31-43) is located at the entrance of the active site cavity. In the corresponding region (42-54) of IMPA2, the residues are disordered and partially form an alpha-helix. The structural difference in the opening of the active site cavity suggests that the substrate specificity differs between IMPA1 and IMPA2. The widely opened cavity of IMPA2 implies that the physiological substrate may be a larger compound than inositol monophosphate. The structure of IMPA2 complexed with Ca2+ revealed two metals and one phosphate binding sites, which were the same sites as in IMPA1 complexed with Mn2+ and phosphate, suggesting that the mechanism of the enzymatic reaction is similar to that of IMPA1. The crystal structures of human IMPA2 are useful for understanding the effect of nonsynonymous polymorphism reported in IMPA2, and will contribute to further functional analyses of IMPA2 that potentially predisposes to the vulnerabilities of bipolar disorder, schizophrenia, and febrile seizures.

Gene polymorphisms and behavior

Genetics has a entered golden post genomic era that promises to greatly improve our understanding of the etiology of complex familial disorders. Many forms of behavior are familial but Mendelian disorders are rare, and common conditions have complex inheritance. Twin and adoption studies confirm that major psychiatric disorders such as schizophrenia and bipolar affective disorder are highly heritable. There is also emerging evidence of some overlap between these disorders. Several susceptibility loci for schizophrenia have been identified, at least one of which is also a susceptibility gene for bipolar disorder. The first susceptibility genes involved in major psychiatric disorders have been identified and more will soon follow with the exploitation of emerging technologies that allow whole genome association studies.

Malic enzyme 2 and susceptibility to psychosis and mania

Previous studies have identified a putative gene locus for both schizophrenia and bipolar disorder in the chromosome 18q21 region. To identify candidate genes associated with these disorders we completed fine mapping analyses (using microsatellite markers) in 152 families from the Central Valley of Costa Rica (CVCR) (376 total subjects, 151 with a history of psychosis, 97 with a history of mania). Microsatellite analyses showed evidence of association at two contiguous markers, both located at the same genetic distance and spanning approximately 11 known genes. In a corollary gene expression study, one of these genes, malic enzyme 2 (ME2), showed levels of gene expression 5.6-fold lower in anterior cingulate tissue from post-mortem bipolar brains. Subsequent analysis of individual SNPs in strong linkage disequilibrium with the ME2 gene revealed one SNP and one haplotype associated with the phenotype of psychosis in the CVCR sample. ME2 interacts directly with the malate shuttle system, which has been shown to be altered in schizophrenia and bipolar disorder, and has roles in neuronal synthesis of glutamate and γ-amino butyric acid. The present study suggests that genetic variation in or near the ME2 gene is associated with both psychotic and manic disorders, including schizophrenia and bipolar disorder.

Association study of polymorphisms in the glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 with schizophrenia

Based on the glutamatergic dysfunction hypothesis for schizophrenia pathogenesis, we have been performing systematic association studies of schizophrenia with the glutamate receptor and transporter genes. We report here association studies of schizophrenia with three glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 encoding the glutamate transporters EAAT3, EAAT1, and EAAT4, respectively. We initially performed the screening of the total 25 single nucleotide polymorphisms (SNPs) distributed in the three gene regions using 100 out of 400 Japanese cases and 100 out of 420 Japanese controls. After controlling the false discovery rate (FDR) at level 0.05, we observed significant associations of schizophrenia with a genotype of SNP4 (rs2097837, P = 0.007) and with haplotypes of SNP2-SNP5 (P = 7.5 x 10(-5)) and SNP3-SNP5 (P = 9.0 x 10(-4)) in the SLC1A6 region. The haplotype of SNP2-SNP5 of SLC1A6 even showed marginally significant association with the disease in the full-size sample (400 cases and 420 controls, P = 0.031). We concluded that at least one susceptibility locus for schizophrenia may be located within or nearby SLC1A6, whereas SLC1A1 and SLC1A3 are unlikely to be major susceptibility genes for schizophrenia in the Japanese population.

Cat Eye Syndrome Associated with Schizophrenia

Schizophrenia is a frequent and complex psychiatric disorder. Current neurobiological research in schizophrenia provides a wealth of information about structural, functional and genetic aspects of the disease [1] . Schizophrenia loci with evidence for linkage can be found on the following chromosal arms: 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20p, 14p, and 2p-q [3] . Deletions, duplications, and translocations of proximal chromosome 22q have been associated with a number of syndromes and developmental abnormalities [6] . The majority of these rearrangements occur within the 22q11.2 region, termed 22q11 deletion syndrome, which is the most common of these. This deletion is associated with several syndromes, including DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes, and in almost all cases involves hemizygosity of the entire 3-Mb typically deleted region. Supernumery marker chromosomes with rearrangement in region 22q11.2 has been associated with cat-eye syndrome (CES) [2, 4] . Previously reported clinical fi ndings for patients with CES include ocular coloboma, down slanting palpebral fi ssures, hypertelorism, preauricular pits and / or tags, cardiac malformations, renal malformations, anal atresia, and normal or only mildly retarded mental development. A 25-year-old female patient, who was diagnosed to have CES associated with biocular coloboma, preauricular pits, hypaccusis, craniofacial malformations and skeletal anomalies was admitted to our hospital because of problems with auditory and coenesthetic hallucinations, bizarre delusions, paranoid ideas and suicidal ideation for the past 6 months. MRI scan showed Klippel – Feil sequence with spina bifi da occulta and neuropsychological testing revealed no cognitive defi cits. Corresponding to cat eye syndrome a cytogenetic analysis showed acrocentric chromosome fragments. Schizophrenia was diagnosed according to DSM-IV criteria and symptoms remitted after 4 weeks of treatment with olanzapine. It has been observed that especially patients with velocardiofacial syndrome, which shows a deletion at 22q11, display increased incidence of schizophrenic psychosis [5] . Recent reports suggest a risk for the deletion at least one order of magnitude greater in schizophrenics than in the general population [5] . Thus it is probable that 22q11.2 contains loci that are associated with or contribute to the development of schizophrenia. Recent studies have confi rmed this hypothesis, and a number of genes including catecholO -methyltransferase within this region have been specifi cally implicated in predicting psychosis [3, 5] . In conclusion, we have reported the fi rst case of schizophrenia in a patient with cat eye syndrome and underline the importance of the 22q11.2 region for the risk of development of the disease. References 1 Gallinat J , Heinz A : Combination of multimodal imaging and molecular genetic information to investigate complex psychiatric disorders . Pharmacopsychiatry 2006 ; 39 (Suppl 1) : 76 – 79 2 Gothelf D , Eliez S , Thompson T , Hinard C , Penniman L , Feinstein C , Kwon H , Jin S , Jo B , Antonarakis SE , Morris MA , Reiss AL : COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome . Nature Neuroscience 2005 ; 8 : 1500 – 1502 3 Maier W , Zobel A , Rietschel M : Genetics of schizophrenia and affective disorders . Pharmacopsychiatry 2003 ; 36 (Suppl 3) : 195 – 202 4 McDermid HE , Morrow BE : Genomic disorders on 22q11 . Am J Hum Genet 2002 ; 70 : 1077 – 1088 5 Murphy KC : Schizophrenia and velo-cardio-facial syndrome . Lancet 2002 ; 359 : 426 – 430 6 Shaikh TH , Kurahashi H , Emanuel BS : Evolutionarily conserved low copy repeats (LCRs) in 22q11 mediate deletions, duplications, translocations, and genomic instability: an update and literature review . Genet Med 2001 ; 3 : 6 – 13

Association study of an (AC)n dinucleotide repeat and schizophrenia in Asian and European populations

Linkage studies have suggested that chromosome 15q13-q14 may harbor a susceptibility locus for schizophrenia. In the current study, the association between a (AC)n dinucleotide repeat polymorphism at D15S118 and schizophrenia was investigated using three independent samples from the Han Chinese population and the Scotland population. In the population-based study, a significant difference was found between the allele frequency distributions in schizophrenia patients and control subjects in the Scottish samples (P = 0.04), but was not replicated in the Chinese samples. In a family-based study, no significant transmission disequilibrium from heterozygous parents to affected offspring was observed. Overall, our results did not support the hypothesis that the (AC)n dinucleotide repeat polymorphism plays a major role in schizophrenia susceptibility, at least in the Chinese population. Further studies are needed to elucidate its role in schizophrenia susceptibility in European population.

Significant Support for DAO as a Schizophrenia Susceptibility Locus: Examination of Five Genes Putatively Associated with Schizophrenia

Schizophrenia is a complex psychiatric disorder with a strong genetic component. Past linkage studies have implicated several chromosomal regions in the etiology of schizophrenia. Within these regions, several genes have been identified via candidate gene association studies as strong schizophrenia susceptibility loci, including DAO, DAOA, DISC1, DTNBP1, and RGS4. The present study attempted to replicate these association findings by analyzing a total of 120 markers across these genes in 311 schizophrenia subjects, 140 schizoaffective subjects, and 291 control subjects. Our study found no association for DAOA and DTNBP1 with schizophrenia. Although no association was seen with DAOA and DTNBP1, several other markers in the other genes resulted in significant association with schizophrenia (p < .05). However, after a conservative Bonferroni correction for multiple testing, only one marker, rs3918346, within DAO remained significant (odds ratio = 1.71, confidence interval = 1.32-2.22, p = 4 x 10(-5)). This significant association was concordant with previous DAO genetic findings. Our results significantly support DAO as a susceptibility locus for schizophrenia and offer some support for the implication of both RGS4 and DISC1 in the etiology of schizophrenia. However, we see no evidence to support either DAOA or DTNBP1 as schizophrenia disease loci.

No association between the CNTF null mutation and schizophrenia or personality

The ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that plays a critical role in neurodevelopment. On the basis of neurodevelopmental hypothesis, the CNTF gene has been a candidate locus for schizophrenia. Several studies have investigated the association between the null mutation of the gene and schizophrenia, however, with inconsistent results. In the present study, we investigated the association in 222 Japanese patients with schizophrenia and 237 controls. The association between the mutation and personality traits was also studied, to investigate the effect of the mutation in participants from the general population. As a result, no association was observed between the mutation and schizophrenia nor personality traits, evaluated by using the Revised NEO Personality Inventory scores. The present study did not provide evidence for the association between the CNTF gene and schizophrenia or personality traits in the Japanese population.

Fine Mapping by Genetic Association Implicates the Chromosome 1q23.3 Gene UHMK1, Encoding a Serine/Threonine Protein Kinase, as a Novel Schizophrenia Susceptibility Gene

Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes. Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects. We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers. These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia.

Genome-wide scan supports the existence of a susceptibility locus for schizophrenia and bipolar disorder on chromosome 15q26

Schizophrenia (SZ) and bipolar disorder (BPD) are two severe psychiatric diseases with a strong genetic component. In agreement with the 'continuum theory', which suggests an overlap between these disorders, the existence of genes that affect simultaneously susceptibility to SZ and BPD has been hypothesized. In this study we performed a 7.5 cM genome scan in a sample of 16 families affected by SZ and BPD, all originating from the same northeast Italian population. Using both parametric and non-parametric analyses we identified linkage peaks on four regions (1p, 1q, 4p and 15q), which were then subjected to a follow-up study with an increased marker density. The strongest linkage was obtained on chromosome 15q26 with a non-parametric linkage of 3.05 for marker D15S1014 (nominal P=0.00197). Interestingly, evidence for linkage with the same marker has been reported previously by an independent study performed on SZ and BPD families from Quebec. In this region, the putative susceptibility gene ST8SIA2 (also known as SIAT8B) was recently associated with SZ in a Japanese sample. However, our allele frequency analyses of the two single-nucleotide polymorphisms (SNPs) with putative functional outcome (rs3759916 and rs3759914) suggest that these polymorphisms are unlikely to be directly involved in SZ in our population. In conclusion, our results support the presence of a gene in 15q26 that influences the susceptibility to both SZ and BPD.

Linkage disequilibrium analyses in the Costa Rican population suggests discrete gene loci for schizophrenia at 8p23.1 and 8q13.3

Linkage studies using multiplex families have repeatedly implicated chromosome 8 as involved in schizophrenia etiology. The reported areas of linkage, however, span a wide chromosomal region. The present study used the founder population of the Central Valley of Costa Rica and phenotyping strategies alternative to DSM-IV classifications in attempts to further delimitate the areas on chromosome 8 that may harbor schizophrenia susceptibility genes. A linkage disequilibrium screen of chromosome 8 was performed using family trios of individuals with a history of psychosis. Four discrete regions showing evidence of association (nominal P values less than 0.05) to the phenotype of schizophrenia were identified: 8p23.1, 8p21.3, 8q13.3 and 8q24.3. The region of 8p23.1 precisely overlaps a region showing strong evidence of linkage disequilibrium for severe bipolar disorder in Costa Rica. The same chromosomal regions were identified when the broader phenotype definition of all individuals with functional psychosis was used for analyses. Stratification of the psychotic sample by history of mania suggests that the 8q13.3 locus may be preferentially associated with non-manic psychosis. These results may be helpful in targeting specific areas to be analyzed in association-based or linkage disequilibrium-based studies, for researchers who have found evidence of linkage to schizophrenia on chromosome 8 within their previous studies.

No evidence for an association between the BDNF Val66Met polymorphism and schizophrenia or personality traits

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family, which plays a critical role in neurodevelopment. Based on the neurodevelopmental hypothesis, the BDNF gene has been a candidate locus for schizophrenia. In Caucasians, recent studies identified an association with the Val66Met polymorphism, which has been suggested to affect episodic memory and hippocampal function in humans. However, in other populations, the association has not been replicated. In the present study, we investigated the association between the Val66Met polymorphism of the gene and schizophrenia in 401 Japanese patients with schizophrenia and 569 controls. As a result, we did not observe a significant difference in genotypic distribution or allele frequencies between the patients and controls ( χ 2 = 0.56, df = 2, p = 0.76 and χ 2 = 0.39, df = 1, p = 0.53, respectively). We also investigated the association between the polymorphism and personality traits in the controls; however, no significant association was observed. Thus, the present study did not provide evidence for an association between the BDNF gene and schizophrenia or personality traits in the Japanese population.

Association analyses suggest GPR24 as a shared susceptibility gene for bipolar affective disorder and schizophrenia

Linkage analyses suggest that chromosome 22q12-13 may harbor a shared susceptibility locus for bipolar affective disorder (BPD) and schizophrenia (SZ). In a study of a sample from the Faeroe Islands we have previously reported association between both disorders and microsatellite markers in a 3.6 cM segment on 22q13. The present study investigated three candidate genes located in this segment: GPR24, ADSL, and ST13. Nine SNPs located in these genes and one microsatellite marker (D22S279) were applied in an association analysis of two samples: an extension of the previously analyzed Faeroese sample comprising 28 distantly related cases (17 BPD, 11 SZ subjects) and 44 controls, and a Scottish sample including 162 patients with BPD, 103 with SZ, and 200 controls. In both samples significant associations were observed in both disorders with predominantly GPR24 SNPs and haplotypes. In the Faeroese sample overall P-values of 0.0009, 0.0054, and 0.0023 were found for haplotypes in BPD, SZ, and combined cases, respectively, and in the Scottish sample overall P-values of 0.0003, 0.0005, and 0.016 were observed for similar groupings. Specific haplotypes showed associations with lowest P-values of 7 x 10(-5) and 0.0006 in the combined group of cases from the Faeroe Islands and Scotland, respectively. The G protein-coupled receptor 24 encoded by GPR24 binds melanin-concentrating hormone (MCH) and has been implicated with feeding behavior, energy metabolism, and regulation of stress and mood. To our knowledge this is the first study reporting association between GPR24 and BPD and SZ, suggesting that GPR24 variants may confer susceptibility to both disorders.

Meta-analysis shows strong positive association of the neuregulin 1 ( NRG1 ) gene with schizophrenia

Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans and confirmed by meta-analysis of published linkage data. Systematic fine mapping using extended Icelandic pedigrees identified an associated haplotype in the gene neuregulin 1 (NRG1), also known as heuregulin, glial growth factor, NDF43 and ARIA. A 290 kb core at risk haplotype at the 5' end of the gene (HAP(ICE)), defined by five SNPs and two microsatellite polymorphisms was found to be associated with schizophrenia in the Icelandic and Scottish populations. A number of subsequent independent studies have attempted to replicate the association, and while some have been successful, the associated haplotype is not always HAP(ICE). Furthermore, no obviously functional or pathogenic variants have been identified, and the relationship between the gene and schizophrenia has remained inconclusive. To reconcile these conflicting findings and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 13 published population-based and family-based association studies up to November 2005. We analysed data from the SNP markers SNP8NRG241930, SNP8NRG243177, SNP8NRG221132 and SNP8NRG221533, and the microsatellite markers 478B14-848, 420M9-1395. Across these studies, strong positive association was found for all six polymorphisms. The haplotype analysis also showed significant association in the pooled international populations (OR=1.22, 95% CI 1.15-1.3, P=8 x 10(-10)). In Asian populations, the risk haplotype was focused around the two microsatellite markers, 478B14-848, 420M9-1395 (haplotype block B), and in Caucasian populations with the remaining four SNP markers (haplotype block A). This meta-analysis supports the involvement of NRG1 in the pathogenesis of schizophrenia, but with association between two different but adjacent haplotypes blocks in the Caucasian and Asian populations.

A further study of a possible locus for schizophrenia on the X chromosome

Several studies suggest that the X chromosome may contain a gene for schizophrenia. In the present study, we recruited 142 male schizophrenic patients and their biological mothers from all parts of the United Kingdom to detect a genetic association for the SYP/CACNA1F locus in the Xp11 region and the FACL4 locus in the Xq22.3–Xq23 region. The haplotype-based haplotype relative risk (HHRR) analysis showed allelic association for rs2071316 ( χ 2 = 6.85, P = 0.009) and rs5905724 ( χ 2 = 5.3, P = 0.021) at the CACNA1F locus, but not for rs5943414 and rs1324805 at the FACL4 locus and rs3817678 at the SYP locus. The haplotype analysis showed a weak association for the rs3817678–rs2071316–rs5905724 haplotypes ( χ 2 = 12.19, df = 4, P = 0.016) but did not show such an association for the rs5943414–rs1324805 haplotypes ( χ 2 = 3.96, df = 2, P = 0.138). Because the linkage disequilibrium signal was detected only at the CACNA1F locus, this gene should perhaps be considered as being a candidate for schizophrenia although further work is needed to draw firm conclusions.

Schizophrenia in an adult with 6p25 deletion syndrome

Chromosomal deletions at 6p25-p24 are rare findings in patients with developmental delay. There is limited information about the adult phenotype. We present a 36-year-old patient with schizophrenia, mild mental retardation, progressive hearing deficits, and characteristic facial features. Ocular (Axenfeld-Rieger anomaly) abnormalities were diagnosed in infancy; vision, however, has remained unimpaired. There were no other major congenital anomalies. Brain imaging showed only minor changes. There was no family history of intellectual deficits or psychosis. Karyotyping revealed a 6p25 deletion, and detailed fluorescence in situ hybridization (FISH) analyses using 23 probes confirmed a 6.7 Mb 6p25-pter deletion. The breakpoint is near a possible 6p25-p24 locus for schizophrenia. Psychotic illness may be part of the neurodevelopmental abnormalities and long-term outcome of patients with 6p terminal deletions. Other similarly affected patients likely remain to be diagnosed in adult populations of schizophrenia and/or mental retardation.

Linkage and association of schizophrenia with genetic variations in the locus of neuregulin 1 in Korean population

Chromosome 8p21-12 has been reported to be a susceptibility locus for schizophrenia based on genome-wide linkage scans. After neuregulin 1 (NRG1) was identified as a positional candidate gene for schizophrenia in this locus, several independent association studies have reported controversial results. To determine whether genetic variations in this locus are associated with schizophrenia in the Korean population, we investigated multiplex families and unrelated patients using linkage and association analyses. Seven microsatellite markers in 8p21-12 were genotyped for 40 families with schizophrenia, and a non-parametric linkage analysis was applied. The association study was performed with 242 unrelated schizophrenia patients and the same number of normal controls for three single nucleotide polymorphisms (SNPs), two microsatellite markers and their haplotypes. A significant linkage signal was observed on D8S1769, which is located 352 kb upstream of the 5' end of the first exon of NRG1 for two ("narrow" and "narrow with auditory hallucination (AH)") of the three adopted phenotype classes. In the association study, the G allele of SNP8NRG241930 was significantly in excess in the subgroup of patients with AHs. We also found haplotypes which were associated with schizophrenia with a protective effect. This study provides additional suggestive evidence for both the linkage and association of genetic variations on 8p12, a locus of NRG1, with schizophrenia. NRG1 might either play a role in the predisposition to schizophrenia or be in linkage disequilibrium (LD) with a causal locus of this illness.

P.1.a.005 Association studies of the CT repeat polymorphism in the cholecystokinin B receptor gene with the diagnosis and the response of pharmacotherapy in Korean patients with panic disorder

Synapsins are synaptic vesicle-associated phosphoproteins and are thought to play crucial roles in synaptogenesis and neurotransmitter release. Synaptic abnormalities have been reported in the pathophysiology of schizophrenia. In addition, the synapsin III gene, a member of the synapsin gene family, has been located at 22q12–13, which has been suggested as a potential susceptibility locus for schizophrenia. We investigated a genetic association between schizophrenia and the synapsin III gene polymorphisms (−631C/G and −196G/A) in 160 schizophrenic patients and 153 controls. No significant positive association between either polymorphism and schizophrenia was observed. Furthermore, no significant association was observed between either polymorphism and the diagnostic subtypes. Our results suggested that the synapsin III gene polymorphisms do not confer increased susceptibility to schizophrenia.

Human QKI, a new candidate gene for schizophrenia involved in myelination

We have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 Mb region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 Mb haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia.