Association Study of 167 Candidate Genes for Schizophrenia Selected by a Multi-Domain Evidence-Based Prioritization Algorithm and Neurodevelopmental Hypothesis

Zhongming Zhao, Bradley T. Webb, Peilin Jia, T.Bernard Bigdeli, Brion S. Maher, Edwin van den Oord, Sarah E. Bergen, Richard L. Amdur, Francis A. O'Neill, Dermot Walsh, Dawn L. Thiselton, Xiangning Chen, Carlos N. Pato, The International Schizophrenia Consortium, Brien P. Riley, Kenneth S. Kendler, Ayman H. Fanous

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Abstract

Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n = 3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein-protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this
ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene Ontology terms related to neurodevelopment. Subsequently, genotypes of 3725 SNPs in 167 genes from a custom Illumina iSelect array were used to evaluate the top ranked vs. hypothesis selected genes. Seventy-three genes were both highly ranked and involved in neurodevelopment (category 1) while 42 and 52 genes were exclusive to neurodevelopment (category 2) or highly ranked (category 3), respectively. The most significant associations were observed in genes PRKG1, PRKCE, and CNTN4 but no individual SNPs were significant after correction for multiple testing. Comparison of the approaches showed an excess of significant tests using the hypothesis-driven neurodevelopment category. Random selection of similar sized genes from two independent genome-wide association studies (GWAS) of schizophrenia showed the excess was unlikely by chance. In a further meta-analysis of three GWAS datasets, four candidate SNPs reached nominal significance. Although gene ranking using integrated sources of prior information did not enrich for significant results in the current experiment, gene selection using an a priori hypothesis (neurodevelopment) was superior to random selection. As such, further development of gene ranking strategies using more carefully selected sources of information is warranted.
Original languageEnglish
Article numbere67776
Pages (from-to)1-8
Number of pages8
JournalPLoS ONE
Volume8
Issue number7
DOIs
Publication statusPublished - 29 Jul 2013

Bibliographical note

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Keywords

  • Algorithms
  • Databases
  • Genetic
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Meta-Analysis as Topic
  • Models
  • Nervous System
  • Polymorphism
  • Single Nucleotide
  • Publishing
  • Schizophrenia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Zhao, Z., Webb, B. T., Jia, P., Bigdeli, T. B., Maher, B. S., van den Oord, E., Bergen, S. E., Amdur, R. L., O'Neill, F. A., Walsh, D., Thiselton, D. L., Chen, X., Pato, C. N., The International Schizophrenia Consortium, Riley, B. P., Kendler, K. S., & Fanous, A. H. (2013). Association Study of 167 Candidate Genes for Schizophrenia Selected by a Multi-Domain Evidence-Based Prioritization Algorithm and Neurodevelopmental Hypothesis. PLoS ONE, 8(7), 1-8. [e67776]. https://doi.org/10.1371/journal.pone.0067776