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

Kurotaki N, Tasaki S, Mishima H, Ono S, Imamura A, Kikuchi T, Nishida N, Tokunaga K, Yoshiura K, Ozawa H - PLoS ONE (2011)

Bottom Line: Only the locus on chromosome 5 has been reported previously.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. naokuro@nagasaki-u.ac.jp

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.

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Related in: MedlinePlus

Two-stage design of this study.A, the first stage was to find an appropriate autosomal run of homozygosity (ROH) size threshold to distinguish specific ROHs from the offspring of first-cousin marriages from ROHs in the offspring of non-consanguineous marriages. The size distribution of ROHs in our non-consanguineous Japanese (non-CJ) and schizophrenia (SCZ) samples was compared. Non-CJ samples are the offspring of non-consanguineous marriages that were validated by interview. Here, SCZ samples were used as the offspring of first-cousin marriages regardless of phenotype. Samples from parents were not used in this study (dashed squares and circles). To confirm our strategy, we also assessed HapMap3 JPT samples, which do not have information for phenotypes or family consanguinity (dashed and solid lines between parents). B, the second stage was to find shared ROHs among the SCZ samples as patients with schizophrenia. In Model I, an autosomal ROH size threshold was applied to filter out smaller ROHs (dashed open boxes). Larger ROHs (solid open boxes) were assessed to find overlaps among patients (solid boxes). In Model II, after filtering by the ROH size threshold, ROHs shared by the siblings of patients and ROHs of other patients were assessed to find overlaps. In this study, the gender of the samples was not matched (diamonds) because we only evaluated autosomal ROHs.
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pone-0020589-g001: Two-stage design of this study.A, the first stage was to find an appropriate autosomal run of homozygosity (ROH) size threshold to distinguish specific ROHs from the offspring of first-cousin marriages from ROHs in the offspring of non-consanguineous marriages. The size distribution of ROHs in our non-consanguineous Japanese (non-CJ) and schizophrenia (SCZ) samples was compared. Non-CJ samples are the offspring of non-consanguineous marriages that were validated by interview. Here, SCZ samples were used as the offspring of first-cousin marriages regardless of phenotype. Samples from parents were not used in this study (dashed squares and circles). To confirm our strategy, we also assessed HapMap3 JPT samples, which do not have information for phenotypes or family consanguinity (dashed and solid lines between parents). B, the second stage was to find shared ROHs among the SCZ samples as patients with schizophrenia. In Model I, an autosomal ROH size threshold was applied to filter out smaller ROHs (dashed open boxes). Larger ROHs (solid open boxes) were assessed to find overlaps among patients (solid boxes). In Model II, after filtering by the ROH size threshold, ROHs shared by the siblings of patients and ROHs of other patients were assessed to find overlaps. In this study, the gender of the samples was not matched (diamonds) because we only evaluated autosomal ROHs.

Mentions: Here, we describe a homozygosity mapping strategy that consisted of 2 stages (Figure 1). The first stage aimed to find the appropriate size threshold for autosomal ROHs that would distinguish ROHs specifically existing in the offspring of first-cousin marriages from those that commonly exist in the offspring of non-consanguineous marriages. By comparing the size distribution of ROHs between the offspring of first-cousin marriages and non-consanguineous marriages, we concluded that ROHs >2.1 Mb in size in the offspring of consanguineous marriages can be assumed to be IBD segments from an individual 3 generations before. The second stage aimed to find shared ROHs among patient with SCZ using 2 models. In Model I, an autosomal ROH size threshold was applied to filter out smaller ROHs. Larger ROHs were assessed to find overlaps among the patients. In Model II, after filtering by the ROH size threshold, ROHs shared by the siblings of patients and ROHs of other patients were assessed to find overlaps. The overlapping ROHs we identified potentially contain SCZ causative regions that are specific to our samples because of the heterogeneous nature of SCZ.


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

Kurotaki N, Tasaki S, Mishima H, Ono S, Imamura A, Kikuchi T, Nishida N, Tokunaga K, Yoshiura K, Ozawa H - PLoS ONE (2011)

Two-stage design of this study.A, the first stage was to find an appropriate autosomal run of homozygosity (ROH) size threshold to distinguish specific ROHs from the offspring of first-cousin marriages from ROHs in the offspring of non-consanguineous marriages. The size distribution of ROHs in our non-consanguineous Japanese (non-CJ) and schizophrenia (SCZ) samples was compared. Non-CJ samples are the offspring of non-consanguineous marriages that were validated by interview. Here, SCZ samples were used as the offspring of first-cousin marriages regardless of phenotype. Samples from parents were not used in this study (dashed squares and circles). To confirm our strategy, we also assessed HapMap3 JPT samples, which do not have information for phenotypes or family consanguinity (dashed and solid lines between parents). B, the second stage was to find shared ROHs among the SCZ samples as patients with schizophrenia. In Model I, an autosomal ROH size threshold was applied to filter out smaller ROHs (dashed open boxes). Larger ROHs (solid open boxes) were assessed to find overlaps among patients (solid boxes). In Model II, after filtering by the ROH size threshold, ROHs shared by the siblings of patients and ROHs of other patients were assessed to find overlaps. In this study, the gender of the samples was not matched (diamonds) because we only evaluated autosomal ROHs.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105082&req=5

pone-0020589-g001: Two-stage design of this study.A, the first stage was to find an appropriate autosomal run of homozygosity (ROH) size threshold to distinguish specific ROHs from the offspring of first-cousin marriages from ROHs in the offspring of non-consanguineous marriages. The size distribution of ROHs in our non-consanguineous Japanese (non-CJ) and schizophrenia (SCZ) samples was compared. Non-CJ samples are the offspring of non-consanguineous marriages that were validated by interview. Here, SCZ samples were used as the offspring of first-cousin marriages regardless of phenotype. Samples from parents were not used in this study (dashed squares and circles). To confirm our strategy, we also assessed HapMap3 JPT samples, which do not have information for phenotypes or family consanguinity (dashed and solid lines between parents). B, the second stage was to find shared ROHs among the SCZ samples as patients with schizophrenia. In Model I, an autosomal ROH size threshold was applied to filter out smaller ROHs (dashed open boxes). Larger ROHs (solid open boxes) were assessed to find overlaps among patients (solid boxes). In Model II, after filtering by the ROH size threshold, ROHs shared by the siblings of patients and ROHs of other patients were assessed to find overlaps. In this study, the gender of the samples was not matched (diamonds) because we only evaluated autosomal ROHs.
Mentions: Here, we describe a homozygosity mapping strategy that consisted of 2 stages (Figure 1). The first stage aimed to find the appropriate size threshold for autosomal ROHs that would distinguish ROHs specifically existing in the offspring of first-cousin marriages from those that commonly exist in the offspring of non-consanguineous marriages. By comparing the size distribution of ROHs between the offspring of first-cousin marriages and non-consanguineous marriages, we concluded that ROHs >2.1 Mb in size in the offspring of consanguineous marriages can be assumed to be IBD segments from an individual 3 generations before. The second stage aimed to find shared ROHs among patient with SCZ using 2 models. In Model I, an autosomal ROH size threshold was applied to filter out smaller ROHs. Larger ROHs were assessed to find overlaps among the patients. In Model II, after filtering by the ROH size threshold, ROHs shared by the siblings of patients and ROHs of other patients were assessed to find overlaps. The overlapping ROHs we identified potentially contain SCZ causative regions that are specific to our samples because of the heterogeneous nature of SCZ.

Bottom Line: Only the locus on chromosome 5 has been reported previously.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropsychiatry, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. naokuro@nagasaki-u.ac.jp

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.

Show MeSH
Related in: MedlinePlus