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Identification of novel schizophrenia loci by homozygosity mapping using DNA microarray analysis.

ABSTRACT: The recent development of high-resolution DNA microarrays, in which hundreds of thousands of single nucleotide polymorphisms (SNPs) are genotyped, enables the rapid identification of susceptibility genes for complex diseases. Clusters of these SNPs may show runs of homozygosity (ROHs) that can be analyzed for association with disease. An analysis of patients whose parents were first cousins enables the search for autozygous segments in their offspring. Here, using the Affymetrix® Genome-Wide Human SNP Array 5.0 to determine ROHs, we genotyped 9 individuals with schizophrenia (SCZ) whose parents were first cousins. We identified overlapping ROHs on chromosomes 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 19, 20, and 21 in at least 3 individuals. Only the locus on chromosome 5 has been reported previously. The ROHs on chromosome 5q23.3-q31.1 include the candidate genes histidine triad nucleotide binding protein 1 (HINT1) and acyl-CoA synthetase long-chain family member 6 (ACSL6). Other overlapping ROHs may contain novel rare recessive variants that affect SCZ specifically in our samples, given the highly heterozygous nature of SCZ. Analysis of patients whose parents are first cousins may provide new insights for the genetic analysis of psychiatric diseases.

SUBMITTER: Kurotaki N

PROVIDER: S-EPMC3105082 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Identification of novel schizophrenia loci by homozygosity mapping using DNA microarray analysis.

Kurotaki Naohiro N Tasaki Shinya S Mishima Hiroyuki H Ono Shinji S Imamura Akira A Kikuchi Taeko T Nishida Nao N Tokunaga Katsushi K Yoshiura Koh-ichiro K Ozawa Hiroki H

PloS one 20110531 5

The recent development of high-resolution DNA microarrays, in which hundreds of thousands of single nucleotide polymorphisms (SNPs) are genotyped, enables the rapid identification of susceptibility genes for complex diseases. Clusters of these SNPs may show runs of homozygosity (ROHs) that can be analyzed for association with disease. An analysis of patients whose parents were first cousins enables the search for autozygous segments in their offspring. Here, using the Affymetrix® Genome-Wide Hum ...[more]

PMID: 21655227

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Project description:Abstract Background Schizophrenia is a highly heritable psychiatric disorder. In the past 30 years, thousands of case-control and family-designed association studies have examined candidate genes for schizophrenia. To assist the field in interpreting this large volume of gene-association studies, the online SzGene database was created and included meta analyses for 287 polymorphisms at the time of its final update in 2010. However, since then more than one-thousand new gene-association studies in schizophrenia have been conducted. As such, we have conducted an updated systematic review and meta-analysis of all gene-association studies in schizophrenia published before March 2017. Methods Studies published between January 2010 and March 2017 were identified using a customized querying strategy. Identified gene-association studies were included in the review and meta-analysis if they: 1) were case-control or family-designed studies with polymorphisms detected in schizophrenia or schizoaffective patients, 2) provide sufficient data to perform meta-analysis, and 3) were not genome-wide association studies (GWAS). Random-effects meta-analysis was performed on polymorphisms with four or more independent studies. Results Raw data of 1711 studies included in the SzGene database were integrated with 1368 studies identified from our systematic literature search. Random-effects meta-analysis were applied to 540 polymorphisms with at least four studies and 89 of these polymorphisms were nominally associated with SZ (unadjusted p < 0.05). After bonferroni correction, 12 polymorphisms remained statistically significant, including five associations not reported in the most recent Psychiatric Genomics Consortium schizophrenia GWAS: 1) rs11098403, p = 1.45e-10, odds ratio = 0.65; 2) rs12807809, p = 7.04e-06, odds ratio = 0.91; 3) rs910694 in PDE4B: p = 1.05e-05, odds ratio = 0.77; 4) rs1801133 in MTHFR: p = 2.99e-05, odds ratio = 1.13 and 5) rs1602565: p = 7.73e-05, odds ratio = 1.11. Discussion Our results provide a comprehensive and up-to-date review of candidate gene association studies in schizophrenia. Findings complement results from GWASs in schizophrenia but also expand the current list of candidate loci for schizophrenia.

Project description:BACKGROUND: Recent transcriptomic analyses in mammals have uncovered the widespread occurrence of endogenous antisense transcripts, termed natural antisense transcripts (NATs). NATs are transcribed from the opposite strand of the gene locus and are thought to control sense gene expression, but the mechanism of such regulation is as yet unknown. Although several thousand potential sense-antisense pairs have been identified in mammals, examples of functionally characterized NATs remain limited. To identify NAT candidates suitable for further functional analyses, we performed DNA microarray-based NAT screening using mouse adult normal tissues and mammary tumors to target not only the sense orientation but also the complementary strand of the annotated genes. RESULTS: First, we designed microarray probes to target the complementary strand of genes for which an antisense counterpart had been identified only in human public cDNA sources, but not in the mouse. We observed a prominent expression signal from 66.1% of 635 target genes, and 58 genes of these showed tissue-specific expression. Expression analyses of selected examples (Acaa1b and Aard) confirmed their dynamic transcription in vivo. Although interspecies conservation of NAT expression was previously investigated by the presence of cDNA sources in both species, our results suggest that there are more examples of human-mouse conserved NATs that could not be identified by cDNA sources. We also designed probes to target the complementary strand of well-characterized genes, including oncogenes, and compared the expression of these genes between mammary cancerous tissues and non-pathological tissues. We found that antisense expression of 95 genes of 404 well-annotated genes was markedly altered in tumor tissue compared with that in normal tissue and that 19 of these genes also exhibited changes in sense gene expression. These results highlight the importance of NAT expression in the regulation of cellular events and in pathological conditions. CONCLUSION: Our microarray platform targeting the complementary strand of annotated genes successfully identified novel NATs that could not be identified by publically available cDNA data, and as such could not be detected by the usual "sense-targeting" microarray approach. Differentially expressed NATs monitored by this platform may provide candidates for investigations of gene function. An advantage of our microarray platform is that it can be applied to any genes and target samples of interest.

Dataset Information

Identification of novel schizophrenia loci by homozygosity mapping using DNA microarray analysis.

Publications

Identification of novel schizophrenia loci by homozygosity mapping using DNA microarray analysis.

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