SYNGR1 is associated with schizophrenia and bipolar disorder in southern India

Chromosome 22q11–13 is one of the most consistent linkage regions for schizophrenia (SCZ) and bipolar disorder (BPAD). The SYNGR1 gene, which is associated with presynaptic vesicles in neuronal cells, is located on 22q13.1. We have previously identified a novel nonsense mutation in the SYNGR1 gene in a SCZ pedigree. In the present study, a detailed analysis of this gene was performed in a case–control cohort (198 BPAD, 193 SCZ and 107 controls from southern India) to test for association with SCZ and BPAD. Sequence analysis of all exonic and flanking intronic regions of the SYNGR1 gene in 198 BPAD and 193 SCZ cases revealed a novel mutation Lsy99Glu (in one BPAD patient) and two other novel common polymorphisms [synonymous single nucleotide polymorphism (SNP—Ser97Ser) and an Asn ins/del] in the SYNGR1 gene. We also validated 9 out of 14 dbSNPs in our population. Case–control analysis revealed allelic (P=0.028–0.00007) association of five polymorphisms with SCZ and/or BPAD cases. Further, 3-SNP (with LD block 1 SNPs) and 2-SNP (with LD block 2 SNPs) haplotype analyses did not show any association with either SCZ or BPAD. Our results support SYNGR1 as a probable susceptibility gene for SCZ and BPAD. Also, the observed association of SYNGR1 with both SCZ and BPAD suggests the likely involvement of a common pathway in the etiology of these disorders.Electronic Supplementary Material Supplementary material is available for this article at     

Insulin-like growth factor 1 (IGF1) polymorphism is associated with Alzheimer's disease in Han Chinese

A review of pathogenic findings in Alzheimer's brains and the functional consequences of altered insulin-like growth factor 1 (IGF1) input to the brain suggest the association between Alzheimer's disease (AD) and the disrupted IGF1 signaling. Recently, the identification of polymorphism rs972936 that was associated with both an increased risk of AD and high circulating levels of IGF1 was reported in Southern European population. In order to evaluate the involvement of the IGF1 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (794 LOAD cases and 796 controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.006, allele P = 0.047). The T allele of rs972936 demonstrated a 1.16-fold risk for developing LOAD when compared with the C allele, which diverges to the report in the Caucasian population. After stratification by apolipoprotein E (APOE) ?4-carrying status, rs972936 polymorphism was only significantly associated with LOAD in non-ApoE ?4 allele carriers (genotype P = 0.002, allele P = 0.039). Multivariate logistic regression analysis also conferred this positive association between the SNP rs972936 and LOAD in the recessive and additive model after adjustment for age, gender, and the ApoE ?4 carrier status. These results suggest that IGF1 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.     

Influence of GRIA1, GRIA2 and GRIA4 polymorphisms on diagnosis and response to antipsychotic treatment in patients with schizophrenia

The present study is aimed at exploring whether some single nucleotide polymorphisms (SNPs) within GRIA1, GRIA2 and GRIA4 could be associated with schizophrenia and whether they could predict clinical outcomes in Korean in-patients treated with antipsychotics. One hundred forty five patients with MD, 221 in-patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for 17 SNPs within GRIA1, GRIA2 and GRIA4. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. No significant association was found with the diagnosis of schizophrenia. We observed an association between rs3813296 genotype and improvement on PANSS negative scores. Our findings provide no evidence for an association between SNPs within GRIA1, GRIA2 and GRIA4 under investigation and schizophrenia susceptibility, although rs3813296 (GRIA2) could be associated with improvement on PANSS negative scores. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.     

Association of DAOA polymorphisms with schizophrenia and clinical symptoms or therapeutic effects

The present study examined the correlation between variants in the d-amino acid oxidase activator (DAOA) locus and clinical symptoms and response to antipsychotics in schizophrenia. Case-control analysis and the family-based association test (FBAT) were performed to investigate whether four single nucleotide polymorphisms (SNPs) at DAOA gene are associated with schizophrenia. The association between the DAOA risk haplotype and clinical symptoms were examined by the positive and negative syndrome scale (PANSS) and the brief psychiatric rating scale (BPRS). Our findings showed that the SNP rs947267 was significantly associated with schizophrenia in both case control and familial trio samples (A>C, chi(2)=8.36, p=0.004; Z=2.335, p=0.019), as well as with specific haplotypes, in particular those formed by the A allele of rs947267. In addition, the risk haplotype AAG was significantly correlated with negative, depression and cognitive impairment factors of PANSS, even with the BPRS change scores after 6-week treatment of atypical antipsychotic drugs (p<0.05). These results support the hypothesis that variations in DAOA may play a role in schizophrenia and clinical characteristics.     

Body mass index is associated with USF1 haplotype in Korean premenopausal women

The upstream stimulatory factor 1 (USF1) gene has been shown to play an essential role as the cause of familial combined hyperlipidemia, and there are several association studies on the relationship between USF1 and metabolic disorders. In this study, we analyzed two single nucleotide polymorphisms in USF1 rs2073653 (306A>G) and rs2516840 (1748C>T) between the case (dyslipidemia or obesity) group and the control group in premenopausal females, postmenopausal females, and males among 275 Korean subjects. We observed a statistically significant difference in the GC haplotype between body mass index (BMI) > or =25 kg/m2) and BMI <25 kg/m2 groups in premenopausal females ( chi2=4.23, p=0.04). It seems that the USF1 GC haplotype is associated with BMI in premenopausal Korean females.     

Genetic variation in GOLM1 and prefrontal cortical volume in Alzheimer's disease

Replications of the association between APOE-ε4 allele load and regional brain atrophy in Alzheimer's disease (AD) patients hold promise for future studies testing relationships between other disease risk gene variants and brain structure. A polymorphism, rs10868366, in the Golgi phosphoprotein 2 gene, GOLM1, was recently identified as an AD risk factor in a genome-wide association study. In a subset of the same AD cohort, we used voxel-based morphometry to test for association between the disease risk genotype and reduced regional gray matter (GM) volume in AD patients (n = 72). A mean 14% reduction in GM volume was observed in the left frontal gyrus with the higher risk GG genotype. A similar association was observed in an independent, dataset of nondemented subjects (n = 278), although with a smaller effect (1%). This replicated association with GM structural variation suggests that GOLM1 polymorphisms may be related to cognitive phenotypes. The greater effect size in AD patients also suggests that the GG genotype could be a risk factor for the expression of cognitive deficits in AD.     

An association study between the genetic polymorphisms within TBX1 and schizophrenia in the Chinese population

The strong association between common psychiatric disorders and the 22q11.2 microdeletion suggests that haploinsufficiency of one or more genes in the region confers susceptibility to these disorders. Recent mouse studies have shown that the T-box 1 (TBX1) gene in the 22q11.2 region can cause prepulse inhibition (PPI) impairment in the heterozygous state. A study has also shown that phenotypic features of 22q11 deletion syndrome (22q11DS) were segregated with an inactivating mutation of TBX1 in one family, suggesting that the TBX1 gene plays a role in the pathogenesis of some psychiatric disorders. We performed an association study between three single nucleotide polymorphisms (SNPs) in the TBX1 gene and schizophrenia. However, we found no significant difference in the genotype or allele distributions between the 328 schizophrenics and 288 controls for any of the polymorphisms, nor was there any haplotype association. Our data suggest that the genetic polymorphisms within TBX1 do not confer an increased susceptibility to schizophrenia in the Chinese population.     

Genetic variations of SOCS1 are associated with chronic hepatitis B virus infection

Suppressor of cytokine signaling (SOCS)-1 is involved in viral infection through regulation of both innate and adaptive immunity. The SOCS1 gene polymorphisms may affect the outcome of viral infection. The relationship between SOCS1 polymorphisms and hepatitis B virus (HBV) infection has not yet been explored. This study genotyped SOCS1 rs243327 and rs33932899 polymorphisms in 477 patients with chronic HBV infection, 93 HBV infection resolvers and 215 healthy controls. In statistical analysis, p-values less than 0.05 in multiple comparisons were corrected by Bonferroni method and presented as p_c. The results showed that the allele T-containing genotypes (CT + TT) of rs243327 were higher in HBV patients than resolvers and lower in resolvers than healthy controls although the difference was not significant. The allele T of rs243327 was significantly lower in resolvers than controls (p = 0.033). The genotype GC and allele C of rs33932899 were significantly less frequent in HBV patients than controls (p_c < 0.001 and p < 0.001, respectively). The haplotype T/G of rs243327/rs33932899 was significantly more frequent in HBV patients than resolvers (p_c < 0.001) or controls (p_c = 0.009). These data indicate that SOCS1 polymorphisms might affect the susceptibility and outcome of HBV infection.     

Exploring the dynamics of P300 amplitude in patients with schizophrenia

This study investigated the time-frequency dynamics of P300 generation in patients with first-onset schizophrenia.A group of 40 patients with first-onset schizophrenia and 40 controls performed an auditory oddball task. Wavelet analysis of the single-trial data was used to compute the Event-Related Spectral Perturbation (ERSP) and the Inter-Trial Phase Coherence (ITC) for the delta, theta, alpha, beta and gamma bands on the 50 ms window around peak P300 amplitude. The contribution of power and synchrony for P300 amplitudes was studied through correlation and regression analysis. Further, two sub-samples in which patients had lower or higher P300 amplitudes than their control match were contrasted.P300 amplitude did not differ between patients and controls. The frequency domain analysis revealed that controls display larger reductions on gamma power than patients. However, this gamma activity might be the result of micro-saccadic muscular artifacts.Regression analysis shows that P300 amplitude is highly dependent on delta power and synchronization. The analysis of the subsamples confirmed that while gamma power differences are dependent on the diagnosis, delta and theta synchronization are related to P300 amplitude, irrespective of diagnosis.     

SORL1 is genetically associated with Alzheimer disease in a Japanese population

A recent study reported that variants of the neuronal sortilin-related receptor gene (SORL1) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-?4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD.     

Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression

Antidepressive medication and electroconvulsive therapy (ECT) increase hippocampal neurogenesis by promoting expression of trophic factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The aims were to test for an association between the VEGF 2578 C/A polymorphism and major depressive disorder (MDD) in two patient populations compared to controls, and the association between this polymorphism and response to serotonin selective reuptake inhibitors (SSRI) and to ECT. The first patient sample consisted of 119 subjects with treatment resistant major depressive disorder who were treated with ECT and the second of 98 depressive patients treated with SSRI. Treatment response was assessed by the Montgomery and Åsberg Depression Rating Scale (MADRS). Patients scoring <8 in post-treatment MADRS were considered remitters. There was a trend that CC genotype of VEGF 2578 C/A polymorphism was more common in ECT-treated and SSRI-treated patients than in controls (31.1%, 25.5% and 18.7% respectively; p = 0.056). The VEGF 2578 C/A polymorphism was associated with treatment resistant MDD. CC genotype was more common in ECT patients than in controls (31.1% and 18.7% respectively; p = 0.015). The VEGF 2578 C/A polymorphism was not associated with treatment response to SSRI or to ECT. The finding suggests an association between VEGF 2578 C/A polymorphism and treatment resistant depression which is reported for the first time. Further studies with larger samples will be required to confirm the results.     

Association and expression study of synapsin III and schizophrenia

The synapsin III gene, SYN3, which belongs to the family of synaptic vesicle-associated proteins, has been implicated in the modulation of neurotransmitter release and in synaptogenesis, suggesting a potential role in several neuropsychiatric diseases. The human SYN3 gene is located on chromosome 22q12-13, a candidate region implicated in previous linkage studies of schizophrenia. However, association studies of SYN3 and schizophrenia have produced inconsistent results. In this study, four SYN3 SNPs (rs133945 (−631 C > G), rs133946 (−196 G > A), rs9862 and rs1056484) were tested in three sets of totally 3759 samples that comprise 655 affected subjects and 626 controls in the Irish Case-Control Study of Schizophrenia (ICCSS), 1350 samples incorporating 273 pedigrees in the Irish Study of High Density Schizophrenia Families (ISHDSF), and 564 unrelated schizophrenia patients and 564 healthy individuals in a Chinese case-control sample. The expression levels of SYN3 in schizophrenic patients and unaffected controls were compared using postmortem brain cDNAs provided by the Stanley Medical Research Institute (SMRI). There was no significant association in either the Irish or Chinese case-control samples, nor in the combined samples. Consistent with this finding, we did not find any significant difference in allele or haplotype frequencies when we used the pedigree disequilibrium test to analyze the Irish family sample. In the expression studies, no significant difference (p = 0.507) was observed between patients and controls. Both the association studies and expression studies didn’t support a major role for SYN3 in the susceptibility of schizophrenia in Irish and Chinese populations.     

ZPLD1 gene is disrupted in a patient with balanced translocation that exhibits cerebral cavernous malformations

The past few years have seen rapid advances in our understanding of the genetics and molecular biology of cerebral cavernous malformations (CCM) with the identification of the CCM1, CCM2, and CCM3 genes. Recently, we have recruited a patient with an X/3 balanced translocation that exhibits CCM. By fluorescent in situ hybridization analysis, sequence analysis tools and database mining procedures, we refined the critical region to an interval of 200-kb and identified the interrupted ZPLD1 gene. We detected that the mRNA expression level of ZPLD1 gene is consistently decreased 2.5-fold versus control (P=0.0006) with allelic loss of gene expression suggesting that this protein may be part of the complex signaling pathway implicated in CCM formation.     

Association analysis of the DISC1 gene with schizophrenia in the Japanese population and DISC1 immunoreactivity in the postmortem brain

The Disrupted-in-Schizophrenia 1 (DISC1) gene plays a role in the regulation of neural development. Previous evidence from genetic association and biological studies implicates the DISC1 gene as having a role in the pathophysiology of schizophrenia. In the present study, we explored the association between DISC1 missense mutation rs821616 (Ser704Cys) single nucleotide polymorphism (SNP) and four other SNPs (rs1772702, rs1754603, rs821621, rs821624) in the related haplotype block and schizophrenia in the Japanese population. We could not find a significant association of selected SNPs with schizophrenia after correction for multiple testing. We performed a meta-analysis of the Ser704Cys variant in schizophrenia using data from the present study and five previous Japanese population studies, and found no association with schizophrenia. We also examined DISC1 immunoreactivity in postmortem prefrontal cortex specimens of schizophrenia patients compared to control samples. The immunoreactivity revealed a significant decrease of DISC1 protein expression in the schizophrenia samples after ruling out potential confounding factors. However, the Ser704Cys variant did not show effects on DISC1 immunoreactivity. These results provide evidence that this functional genetic variation of DISC1 do not underlie the pathophysiology of schizophrenia in the Japanese population.     

Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10⁻⁷, and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10⁻⁷, respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10⁻³). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.     

Polymorphisms in LMNA and near a SERPINA13 gene are not associated with cognitive performance in Chinese elderly males without dementia

Aging is associated with cognitive deterioration. A recent study showed two polymorphisms (rs505058 in LMNA and rs11622883 near a SERPINA13 gene), identified in a genome-wide association study of late-onset Alzheimer's disease, to be associated with cognitive function (Mini Mental State Examination) in a UK elderly population. This study replicated these findings in Chinese elderly males without dementia. A total of 358 elderly subjects were assessed by the Cognitive Abilities Screening Instruments (CASI) and the Wechsler Digit Span Task tests. Analysis of covariance was used to compare cognitive scores among genotypic groups, with age and total education years as covariates. The two polymorphisms were not associated with the global cognitive function or specific cognitive domains in the elderly without dementia. Our data argue against that these two polymorphisms may affect cognitive function in the elderly.     

CGG-repeat expansion in FMR1 is not associated with amyotrophic lateral sclerosis

Recently, repeat expansions in several genes have been shown to cause or be associated with amyotrophic lateral sclerosis (ALS). It has been demonstrated that an intronic hexanucleotide repeat expansion in C9ORF72 is a major cause of both familial (approximately 40%) and sporadic (approximately 5%) ALS, as well as frontotemporal dementia (FTD). In addition, a CAG-repeat expansion in exon 1 of ATXN2, otherwise known to cause spinocerebellar ataxia type 2, has been identified as a major risk factor for sporadic ALS. Intermediate repeat expansions in the fragile X mental retardation 1 (FMR1) gene (55-200 repeats) are known to cause fragile X-associated premature ovarian insufficiency [(FX)POI; female carriers] or fragile X-associated tremor/ataxia syndrome (FXTAS; male carriers) by CGG-mediated RNA toxicity. The present investigation involves screening FMR1 repeat length in 742 sporadic ALS patients and 792 matched controls. Our conclusion is that FMR1 repeat expansions are not associated with ALS.     

MASP2 haplotypes are associated with high risk of cardiomyopathy in chronic Chagas disease

Mannose-binding lectin (MBL) initiates complement on Trypanosoma cruzi through the MBL-associated serine protease 2 (MASP2). We haplotyped six MASP2 polymorphisms in 208 chronic chagasic patients, being 81 indeterminate and 123 symptomatic (76 with cardiac, 19 with digestive and 28 with cardiodigestive forms) and 300 healthy individuals from Southern Brazil, using PCR with sequence-specific primers. The g.1961795C, p.371D diplotype (short CD) occurred at a higher frequency among symptomatic patients, compared with the indeterminate group (P(Bf)=0.012, OR=3.11), as well as genotypes with CD, but not with the g.1945560A in the promoter in cardiac patients (P(Bf)=0.012, OR=13.54). CD haplotypes linked to the p.P126L and p.V377A variants were associated with reduced MASP-2 levels (P<0.0001) but not reduced MBL/MASP-2/C4 complexes. MASP2*CD genotypes, most of them generating low MASP-2 levels, are associated with high risk of chagasic cardiomyopathy. Rapid MASP2 genotyping might be used to predict the risk of symptomatic disease.