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.

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    ABSTRACT: BackgroundTerminal deletions of chromosome 4q are associated with a broad spectrum of phenotypes including cardiac, craniofacial, digital, and cognitive impairment. The rarity of this syndrome renders genotype-phenotype correlation difficult, which is further complicated by the widely different phenotypes observed in patients sharing similar deletion intervals.Case presentationHerein, we describe a boy with congenital hearing impairment and a variety of moderate syndromic features that prompted SNP array analysis disclosing a heterozygous 6.9 Mb deletion in the 4q35.1q35.2 region, which emerged de novo in the maternal germ line.ConclusionIn addition to the index patient, we review 35 cases from the literature and DECIPHER database to attempt genotype-phenotype correlations for a syndrome with great phenotypic variability. We delineate intervals with recurrent phenotypic overlap, particularly for cleft palate, congenital heart defect, intellectual disability, and autism spectrum disorder. Broad phenotypic presentation of the terminal 4q deletion syndrome is consistent with incomplete penetrance of the individual symptoms.
    BMC Medical Genetics 06/2014; 15(1):72. DOI:10.1186/1471-2350-15-72 · 2.45 Impact Factor
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    ABSTRACT: BackgroundExpression quantitative trait loci (eQTL) are genomic regions regulating RNA transcript expression levels. Genome-wide Association Studies (GWAS) have identified many variants, often in non-coding regions, with unknown functions and eQTL provide a possible mechanism by which these variants may influence observable phenotypes. Limited access and availability of tissues such as brain has led to the use of blood as a substitute for eQTL analyses.MethodsHere, we evaluate the overlap of eQTL reported in published studies conducted in blood and brain tissues to assess the utility of blood as an alternative to brain tissue in the study of neurological and psychiatric conditions. Expression QTL results from eight published brain studies were compared to blood eQTL identified in from a meta-analysis involving 5,311 individuals. We accounted for differences in SNP platforms and study design by using SNP proxies in high linkage disequilibrium with reported eQTL. The degree of overlap between studies was calculated by ascertaining if an eQTL identified in one study was also identified in the other study.ResultsThe percentage of eQTL overlapping for brain and blood expression after adjusting for differences in sample size ranged from 13 - 23% (mean 19.2%). Amongst pairs of brain studies eQTL overlap ranged from 0 - 35%, with higher degrees of overlap found for studies using expression data collected from the same brain region.ConclusionOur results suggest that whenever possible tissue specific to the pathophysiology of the disease being studied should be used for transcription analysis.
    BMC Medical Genomics 06/2014; 7(1):31. DOI:10.1186/1755-8794-7-31 · 3.91 Impact Factor
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