Article

Genome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia

Department of Psychiatry and Human Behavior, Functional Genomics Laboratory, College of Medicine, University of California, Irvine, CA 92697, USA.
Human Genetics (Impact Factor: 4.52). 07/2006; 119(5):558-70. DOI: 10.1007/s00439-006-0172-7
Source: PubMed

ABSTRACT Multiple linkage regions have been reported in schizophrenia, and some appear to harbor susceptibility genes that are differentially expressed in postmortem brain tissue derived from unrelated individuals. We combined traditional genome-wide linkage analysis in a multiplex family with lymphocytic genome-wide expression analysis. A genome scan suggested linkage to a chromosome 4q marker (D4S1530, LOD 2.17, theta = 0) using a dominant model. Haplotype analysis using flanking microsatellite markers delineated a 14 Mb region that cosegregated with all those affected. Subsequent genome-wide scan with SNP genotypes supported the evidence of linkage to 4q33-35.1 (LOD = 2.39) using a dominant model. Genome-wide microarray analysis of five affected and five unaffected family members identified two differentially expressed genes within the haplotype AGA and GALNT7 (aspartylglucosaminidase and UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 7) with nominal significance; however, these genes did not remain significant following analysis of covariance. We carried out genome-wide linkage analyses between the quantitative expression phenotype and genetic markers. AGA expression levels showed suggestive linkage to multiple markers in the haplotype (maximum LOD = 2.37) but to no other genomic region. GALNT7 expression levels showed linkage to regulatory loci at 4q28.1 (maximum LOD = 3.15) and in the haplotype region at 4q33-35.1 (maximum LOD = 2.37). ADH1B (alcohol dehydrogenase IB) was linked to loci at 4q21-q23 (maximum LOD = 3.08) and haplotype region at 4q33-35.1 (maximum LOD = 2.27). Seven differentially expressed genes were validated with RT-PCR. Three genes in the 4q33-35.1 haplotype region were also differentially expressed in schizophrenia in postmortem dorsolateral prefrontal cortex: AGA, HMGB2, and SCRG1. These results indicate that combining differential gene expression with linkage analysis may help in identifying candidate genes and potential regulatory sites. Moreover, they also replicate recent findings of complex trans- and cis- regulation of genes.

Download full-text

Full-text

Available from: Ling Shao, Jul 03, 2014
0 Followers
 · 
121 Views
  • Source
    • "CD14 antigen, chemokine receptor 1) Zvara et al., 2005 Lymphocytes 13 drug-naïve/drug-free schizophrenia patients Genes for dopamine receptor D2 (DRD2) and the inwardly rectifying potassium channel (Kir2.3) were over-expressed Vawter et al., 2006 Lymphocytes Multiplex pedigree study of 5 haplotype-positive individuals with schizophrenia, 5 unaffected haplotype-negative controls AGA expression levels showed suggestive linkage to multiple markers in the haplotype; GALNT7 expression levels showed linkage to regulatory loci at 4q28.1 and in the haplotype region at 4q33−35.1 Bowden et al., 2006 Lymphocytes 14 schizophrenia and 14 matched controls 18 genes with brain-related functions were altered in schizophrenia versus controls; 4 of which, endothelial differentiation gene 2 (Edg-2), ezrin-radixin-moesin phosphoprotein 50 (EBP50), myc-associated zinc finger protein (MAZ) and tumor necrosis factor receptor 2 (TNFR2), were confirmed by relative real-time PCR McCurdy et al., 2006 Olfactory neuroepithelium 10 schizophrenia, 8 bipolar and 9 matched control subjects Genes associated with vesicle-mediated transport, cell proliferation, neurogenesis, apoptosis and inositol phosphate metabolism/ phosphatidylinositol signalling were most significantly dysregulated in schizophrenia Matigian et al., 2008 Lymphoblasts and fibroblasts 16 schizophrenia patients and 14 matched controls No significantly different expression in schizophrenia versus controls Yao et al., 2008 Blood mononuclear cells 30 first-admission schizophrenia patients and 26 healthy control subjects Increased chemokine (C-X-C motif) ligand 1 (CXCL1) expression in schizophrenia confirming findings reported by Tsuang et al. (2005) Glatt et al., 2009 Blood mononuclear cells 13 schizophrenia, 9 bipolar disorder and 8 healthy control subjects Significant interaction between diagnostic group and exon identity, with 33 genes showing differential splicing patterns between schizophrenia and bipolar disorder samples Bousman et al., 2010 Blood mononuclear cells 24 schizophrenia, 23 bipolar disorder, 25 h10 91/F6 nonuclear cellsdep1 Trourder andy, with 33 genes "
    [Show abstract] [Hide abstract]
    ABSTRACT: With an estimated 80% heritability, molecular genetic research into schizophrenia has remained inconclusive. Recent large-scale, genome-wide association studies only identified a small number of susceptibility genes with individually very small effect sizes. However, the variable expression of the phenotype is not well captured in diagnosis-based research as well as when assuming a 'heterogenic risk model' (as apposed to a monogenic or polygenic model). Hence, the expression of susceptibility genes in response to environmental factors in concert with other disease-promoting or protecting genes has increasingly attracted attention. The current review summarises findings of microarray gene expression research with relevance to schizophrenia as they emerged over the past decade. Most findings from post mortem, peripheral tissues and animal models to date have linked altered gene expression in schizophrenia to presynaptic function, signalling, myelination, neural migration, cellular immune mechanisms, and response to oxidative stress consistent with multiple small effects of many individual genes. However, the majority of results are difficult to interpret due to small sample sizes (i.e. potential type-2 errors), confounding factors (i.e. medication effects) or lack of plausible neurobiological theory. Nevertheless, microarray gene expression research is likely to play an important role in the future when investigating gene/gene and gene/environment interactions by adopting a neurobiologically sound theoretical framework.
    Australian and New Zealand Journal of Psychiatry 03/2012; 46(7):598-610. DOI:10.1177/0004867412442405 · 3.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT Wehave,previously ,found ,that variation ,in alcohol ,metabolism ,in Europeans ,is linked to the,chromosome,4q region,containing,the ADH gene,family. We have,now typed,103 SNPs across ,this region ,to test ,for allelic associations ,with ,variation ,in blood,and ,breath ,alcohol ,concentrations after an alcohol challenge. In vivo ,alcohol metabolism,was ,modelled ,with three parameters that identified the absorption ,and rise of alcohol concentration following ingestion, and the rate of elimination. Alleles of ADH7 SNPs were associated with the early stages of alcohol metabolism, with additional effects in the ADH1A, ADH1Band ADH4regions. Rate of elimination was associated with SNPs in the intragenic region between ADH7and ADH1C, and across ADH1C and,ADH1B. SNPs affecting alcohol,metabolism did,not correspond,to those reported,to affect,alcohol dependence,or alcohol-related disease. The combined,SNP
  • Source
Show more