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Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance.

ABSTRACT: The genetic region coding for d-amino acid oxidase activator (DAOA) is considered an intriguing susceptibility locus for schizophrenia. However, association studies have often resulted in conflicting findings, and the risk-conferring variants and their biological impact remain elusive. Our aim in this study was to investigate the relationship between DAOA variation and schizophrenia, and the influence of DAOA on cognitive performance.We analyzed block structure and association patterns of an approximately 173 kb region on chromosome 13q33, applying genotype data of 55 SNPs derived from Caucasian North American sample (178 cases, 144 healthy controls). Haplotypes were assigned using the program PHASE and frequencies compared between cases and controls. We applied MANOVA to investigate the relationship between the identified risk haplotype on cognitive performance.We identified multiple haplotypes within the region containing the DAOA gene. Of these, one was significantly associated with schizophrenia, being over-represented in schizophrenia versus healthy controls. This haplotype was also associated with one aspect of cognitive performance, semantic fluency. Carriers of the risk haplotype showed better semantic fluency than non-carriers.We report a significant effect of DAOA variation on risk for schizophrenia. Moreover, we identified a relationship between DAOA genetic variation and specific aspects of neurocognitive function. As the identified DAOA risk haplotype was associated with better performance on a semantic fluency measure, further work is required to identify the mechanism of DAOA action on CNS function, including the possibility of a role for balanced selection at this locus.

SUBMITTER: Opgen-Rhein C

PROVIDER: S-EPMC2605318 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance.

Opgen-Rhein Carolin C Lencz Todd T Burdick Katherine E KE Neuhaus Andres H AH DeRosse Pamela P Goldberg Terry E TE Malhotra Anil K AK

Schizophrenia research 20080609 1-3

<h4>Introduction</h4>The genetic region coding for d-amino acid oxidase activator (DAOA) is considered an intriguing susceptibility locus for schizophrenia. However, association studies have often resulted in conflicting findings, and the risk-conferring variants and their biological impact remain elusive. Our aim in this study was to investigate the relationship between DAOA variation and schizophrenia, and the influence of DAOA on cognitive performance.<h4>Methods</h4>We analyzed block structu ...[more]

PMID: 18541412

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Project description:Abstract Background D-amino acid oxidase activator (DAOA) gene, which plays a key role in glutamatergic transmission and mitochondrial function, is frequently linked with the liability for schizophrenia. In this study, we aimed to investigate whether the variation of DAOA rs2391191 could be associated with alterations in white matter integrity in first episode schizophrenia patients, and whether it influences the association between white matter integrity, cognitive function and clinical symptoms of schizophrenia. Methods Forty-six patients with first-episode schizophrenia and forty-nine sex, age and education-matched healthy controls underwent diffusion tensor imaging (DTI) and were genotyped for SNP DAOA rs2391191. Tract-based spatial statistics (TBSS) was used to delineate the major fiber tracts that showed significant group difference. Patients underwent pathophysiological assessments using Brief Psychiatric Rating Scale (BPRS) and Scale for Assessment of Negative Symptoms (SANS). Cognitive function assessments were performed by Chinese version of the MATRICS Consensus Cognitive Battery (MCCB). Results Schizophrenia patients presented lower fractional anisotropy (FA) and higher radial diffusivity (RD) mainly spreading over corpus callosum and corona radiata compared with healthy controls (FWE-corrected p<0.05). Compared with patients carrying G allele, patients with AA genotype showed lower FA in body of corpus callosum, and higher RD in genu of corpus callosum, right superior and anterior corona radiata, and left posterior corona radiata. But there were no significant FA or RD differences between two genotype groups in healthy controls. In patients carrying G allele, mean FA values in body of corpus callosum were positively correlated with working memory, mean RD values in genu of corpus callosum were negatively associated with speed of processing, working memory and composite score of MATRICS Consensus Cognitive Battery (MCCB), whilst there were no significant correlations found in AA homozygotes. Discussion Abnormal white matter integrity in corpus callosum and corona radiata were replicated among our sample of first episode schizophrenia. Genetic variation of DAOA rs2391191 was associated with this abnormality, with AA homozygotes showing less white matter integrity in corpus callosum. Our findings also suggested that rs2391191influenced the association between white matter integrity and cognitive function of schizophrenia patients. Such results might be due to the process of glutamatergic neurotransmission and mitochondrial function DAOA involves in as pinpointed by previous in vitro studies.

Project description:Toll-like receptors (TLRs) are expressed not only in immune cells but also in a variety of tumor cells. Single-nucleotide polymorphisms (SNPs) located in the TLRs' promoter or the 3' untranslated region may affect gene expression by affecting the activity of the promoter or regulating the binding of mRNA to miRNA. This study aimed to investigate the association of the SNPs in TLR genes with the susceptibility to NSCLC. This case-control study involved 700 lung cancer patients and 700 healthy controls. All individuals were genotyped for all selected SNPs in TLR genes using polymerase chain reaction (PCR) test-based restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP genotyping assay. The association of genetic variations in TLRs with the susceptibility to NSCLC was evaluated by unconditional logistic regression with OR (95% CI). After evaluating transcriptional factor or miRNA binding capability by bioinformatics methods, six TLRs were identified for further analysis. We did not find that TLR3 rs5743303, TLR4 rs1927914, TLR4 rs11536891, TLR5 rs1640816, and TLR7 rs3853839 were associated with NSCLC risk (P > 0.05). Our data showed that TLR4 rs7869402?C?>?T polymorphism reduced the risk of NSCLC with OR (95% CI) of 0.63 (0.45-0.89). When stratified by gender and age, the individuals carrying at least one rs7869402T allele significantly decreased the NSCLC risk among males (OR?=?0.58, 95% CI?=?0.38-0.87) and among youngsters (OR?=?0.43, 95% CI?=?0.27-0.69). Smoking stratification analysis showed that the rs7869402T allele-containing genotype reduced the risk of NSCLC with OR (95% CI) of 0.50 (0.29-0.87) among smokers but not among nonsmokers (P > 0.05). When the individuals were classed by the pathological type, we found that the rs7869402T-containing genotype was associated with the risk of adenocarcinoma (OR?=?0.62, 95% CI?=?0.41-0.92) but not with that of squamous cell carcinoma (OR?=?0.71, 95% CI?=?0.44-1.13) and other types (OR?=?0.23, 95% CI?=?0.03-1.70). Compared with the TLR4 Ars1927914-Crs7869402-Trs11536891 haplotype, the Grs1927914-Trs7869402-Trs11536891 haplotype was associated with a decreased risk for developing NSCLC with OR (95% CI) of 0.57 (0.41-0.80). These results indicated that the TLR4 rs7869402 variation affects the genetic susceptibility to NSCLC.

Project description:Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population.

Dataset Information

Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance.

Publications

Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance.

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