Evidence for the association of the DAOA (G72) gene with schizophrenia and bipolar disorder but not for the association of the DAO gene with schizophrenia

Background: Previous linkage and association studies have implicated the D-amino acid oxidase activator gene (DAOA)/G30 locus or neighbouring region of chromosome 13q33.2 in the genetic susceptibility to both schizophrenia and bipolar disorder. Four single nucleotide polymorphisms (SNPs) within the D-amino acid oxidase (DAO) gene located at 12q24.11 have also been found to show allelic association with schizophrenia.Methods: We used the case control method to test for genetic association with variants at these loci in a sample of 431 patients with schizophrenia, 303 patients with bipolar disorder and 442 ancestrally matched supernormal controls all selected from the UK population.Results: Ten SNPs spanning the DAOA locus were genotyped in these samples. In addition three SNPs were genotyped at the DAO locus in the schizophrenia sample. Allelic association was detected between the marker rs3918342 (M23), 3' to the DAOA gene and both schizophrenia (chi(2) = 5.824 p = 0.016) and bipolar disorder (chi(2) = 4.293 p = 0.038). A trend towards association with schizophrenia was observed for two other DAOA markers rs3916967 (M14, chi(2) = 3.675 p = 0.055) and rs1421292 (M24; chi(2) = 3.499 p = 0.062). A test of association between a three marker haplotype comprising of the SNPs rs778293 (M22), rs3918342 (M23) and rs1421292 (M24) and schizophrenia gave a global empirical significance of p = 0.015. No evidence was found to confirm the association of genetic markers at the DAO gene with schizophrenia.Conclusion: Our results provide some support for a role for DAOA in susceptibility to schizophrenia and bipolar disorder

Failure to confirm allelic and haplotypic association between markers at the chromosome 6p22.3 dystrobrevin-binding protein 1 (DTNBP1) locus and schizophrenia

Background: Previous linkage and association studies may have implicated the Dystrobrevin-binding protein 1 (DTNBP1) gene locus or a gene in linkage disequilibrium with DTNBP1 on chromosome 6p22.3 in genetic susceptibility to schizophrenia.Methods: We used the case control design to test for of allelic and haplotypic association with schizophrenia in a sample of four hundred and fifty research subjects with schizophrenia and four hundred and fifty ancestrally matched supernormal controls. We genotyped the SNP markers previously found to be significantly associated with schizophrenia in the original study and also other markers found to be positive in subsequent studies.Results: We could find no evidence of allelic, genotypic or haplotypic association with schizophrenia in our UK sample.Conclusion: The results suggest that the DTNBP1 gene contribution to schizophrenia must be rare or absent in our sample. The discrepant allelic association results in previous studies of association between DTNBP1 and schizophrenia could be due population admixture. However, even positive studies of European populations do not show any consistent DTNBP1 alleles or haplotypes associated with schizophrenia. Further research is needed to resolve these issues. The possible confounding of linkage with association in family samples already showing linkage at 6p22.3 might be revealed by testing genes closely linked to DTNBP1 for allelic association and by restricting family based tests of association to only one case per family

Mosaic copy number variation in schizophrenia

Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n=3518; control, n=4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects

An integrated genetic-epigenetic analysis of schizophrenia : evidence for co-localization of genetic associations and differential DNA methylation

Background: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.Peer reviewe

An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis

FUNDING Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. ACKNOWLEDGEMENTS The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank Akira Sawa and Koko Ishzuki for advice on the PAK7–DISC1 interaction experiment and Jan Korbel for discussions on mechanism of structural variation.Peer reviewedPublisher PD

A Comprehensive Family-Based Replication Study of Schizophrenia Genes

Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets

A Rare Functional Noncoding Variant at the GWAS-Implicated MIR137/MIR2682 Locus Might Confer Risk to Schizophrenia and Bipolar Disorder

Schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ∼6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10−4). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches

Rare chromosomal deletions and duplications increase risk of schizophrenia

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73 - 90% ( ref. 1). Inheritance patterns are complex, ..