Genomic Convergence Analysis of Schizophrenia: mRNA Sequencing Reveals Altered Synaptic Vesicular Transport in Post-Mortem Cerebellum

Mudge, Joann; Miller, Neil; Khrebtukova, Irina; Lindquist, Ingrid; May, Gregory D.; Huntley, James S; Luo, Shujun; Zhang, Lu; Velkinburgh, Jennifer C. van; Farmer, Andrew; Lewis, Sharon; Beavis, William D.; Schilkey, Faye; Virk, Selene; Black, C. Forrest; Myers, Margaret; Mader, Lar C.; Langley, Ray J.; Utsey, John P; Kim, Ryan W.; Roberts, Rosalinda C.; Khalsa, Sat Kirpal; Garcia, Meredith M.; Ambriz-Griffith, Victoria; Harlan, Richard E.; Czika, Wendy; Martin, Stanton; Wolfinger, Russell D.; Perrone‐Bizzozero, Nora I.; Schroth, Gary P.; Kingsmore, Stephen F.

doi:10.1371/journal.pone.0003625

Cited by 110 publications

(118 citation statements)

References 82 publications

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“…8,9 Differences in the expression of genes involved in Golgi function and vesicular transport in the presynapse have been reported in the postmortem cerebellar cortex of schizophrenia patients. 3 In conclusion, this case-control study suggests involvement of dymeclin in the susceptibility to schizophrenia. …”

Section: Discussionmentioning

confidence: 54%

“…In a recent study, 3 in which mRNA abundance was determined by sequencing mRNA in postmortem cerebellum, gene ontology annotation of genes with significantly altered expression revealed overrepresentation of membrane-associated genes, genes involved in zinc binding or transport, regulation of transcription, Golgi apparatus and vesicle-mediated transport. The authors mentioned that most striking were 23 genes involved in presynaptic vesicular transport/ Golgi apparatus or postsynaptic neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

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An association study between the dymeclin gene and schizophrenia in the Japanese population

et al. 2010

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Many gene variants are involved in the susceptibility to schizophrenia and some of them are expected to be associated with other human characters. Recently reported meta-analysis of genetic associations revealed nucleotide variants in synaptic vesicular transport/Golgi apparatus genes with schizophrenia. In this study, we selected the dymeclin gene (DYM) as a candidate gene for schizophrenia. The DYM gene encodes dymeclin that has been identified to be associated with the Golgi apparatus and with transitional vesicles of the reticulum-Golgi interface. A three-step case-control study of total of 2105 Japanese cases of schizophrenia and 2087 Japanese control subjects was carried out for tag single-nucleotide polymorphisms (SNPs) in the DYM gene and an association between an SNP, rs833497, and schizophrenia was identified (allelic P¼2Â10 À5 , in the total sample). DYM is the causal gene for Dyggve-Melchior-Clausen syndrome and this study shows the second neuropsychiatric disorder in which the DYM gene is involved. The present data support the involvement of Golgi function and vesicular transport in the presynapse in schizophrenia.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

An association study between the dymeclin gene and schizophrenia in the Japanese population

et al. 2010

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“…Short-insert, paired-read libraries were generated from mRNA as described (15). Singleton 36 nucleotide reads were generated using Illumina GAII instruments as described (15).…”

Section: Methodsmentioning

confidence: 99%

“…Sequences were aligned to the NCBI human reference, version 36.2, with GSNAP (16). SNVs were identified using optimized filters with the Alpheus software system (11,15,17). Putative SNVs were validated by targeted Sanger PCR and cycle sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…2) with the intent of using deep sequencing to both detect and enumerate the frequency of expressed mutations, including those present in minority subpopulations of a tumor. RNA from matched normal and tumor specimens from an endometrial cancer patient was sequenced by mRNA-seq, yielding approximately 1 billion nucleotides of 36 bp singleton reads from each (15). Using the Alpheus pipeline, ~80% of reads aligned to the NCBI human genome reference and are available at http://citrine.…”

Section: Deep Transcript Sequencing Identifies the Mutations Uniquelymentioning

confidence: 99%

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Development of a phylogenetic tree model to investigate the role of genetic mutations in endometrial tumors

Zhang

Beck²,

Luo³

et al. 2011

Oncol Rep

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Abstract. With the advancement of modern genome sequencing technology, thousands of genetic mutations have been identified in human tumors. However, analysis of the role of genetic mutations in tumor development is limited by the need for prevalence information among multiple tumors and by the lack of analytic capability to define the functional contribution of genetic mutations in patients, individually and collectively. To understand the genetic basis of human endometrial cancer, the fourth most common cancer in women, transcriptome sequencing was performed on an endometrial tumor paired with normal cervical tissue. Twenty-six nonsynonymous somatic mutations were validated in the tumor genome. A phylogenetic tree illustrating the mutational timeline was developed based upon the distribution of 26 mutations in 30 randomly-selected laser-captured single cells from the tumor sections. Five ubiquitous mutations were identified that are presumed to occur in the cancer founder cell of the tumor, and may collectively play critical roles in endometrial oncogenesis. However, further testing in 10 additional endometrial tumors failed to show overlapping mutations in the cancer founder cells, indicating the lack of a single common oncogenic pathway for these endometrial tumors. The effects of individual mutations in cancer cell proliferation were calculated based on descendant cell number and time span since acquiring each mutation. We have developed a phylogenetic approach to characterize individual genetic mutations in cancer cell proliferation in a single resected patient tumor. This approach provides the capability to study the tumor-specific role of genetic mutations, without relying on prevalence information from other patients.

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Population‐Based Case‐Control Association Studies

Hancock

Scott

2012

CP Human Genetics

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This unit provides an overview of the design and analysis of population-based case-control studies of genetic risk factors for complex disease. Considerations specific to genetic studies are emphasized. The unit reviews basic study designs differentiating case-control studies from others, presents different genetic association strategies (candidate gene, genome-wide association, and high-throughput sequencing), introduces basic methods of statistical analysis for case-control data and approaches to combining case-control studies, and discusses measures of association and impact. Admixed populations, controlling for confounding (including population stratification), consideration of multiple loci and environmental risk factors, and complementary analyses of haplotypes, genes, and pathways are briefly discussed. Readers are referred to basic texts on epidemiology for more details on general conduct of case-control studies.

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Genomic Convergence Analysis of Schizophrenia: mRNA Sequencing Reveals Altered Synaptic Vesicular Transport in Post-Mortem Cerebellum

Cited by 110 publications

References 82 publications

An association study between the dymeclin gene and schizophrenia in the Japanese population

An association study between the dymeclin gene and schizophrenia in the Japanese population

Development of a phylogenetic tree model to investigate the role of genetic mutations in endometrial tumors

Population‐Based Case‐Control Association Studies

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