Expression profiles of schizophrenia susceptibility genes during human prefrontal cortical development

Expression profiles of schizophrenia susceptibility genes during human prefrontal cortical development

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J Psychiatry Neurosci 2009; 34(6): 450-458

Kwang H. Choi, PhD; Megan E. Zepp, BSc; Brandon W. Higgs, PhD; Cynthia S. Weickert, PhD; Maree J. Webster, PhD

Choi, Zepp, Webster — Stanley Medical Research Institute, Rockville, Md.; Higgs — Elashoff Consulting, Redwood City, Calif.; Weickert — Schizophrenia Research Institute, University of New South Wales, Prince of Wales Medical Research Institute, Sydney, Australia

Abstract

Background: Disruption in normal development of the human prefrontal cortex (PFC) may lead to cognitive dysfunction that manifests in individuals with schizophrenia. We sought to identify genes associated with age that are implicated in schizophrenia.

Methods: We generated genome-wide expression profiles for the PFCs of humans ranging in age from 1 month to 49 years using the Affymetrix HG-U133 plus 2.0 microarrays (54 675 transcripts). Based on the criteria of significance (false discovery rate [FDR]-adjusted q < 0.001 and r2 > 0.6), we identified the genes associated with age in the PFC. We then performed functional annotation analyses of age-associated genes using the Gene Ontology and the Genetic Association Database (GAD).

Results: We found robust age-dependent changes in gene expression in the PFCs of humans (2281 transcripts). The GAD analysis revealed that schizophrenia was an over-represented disease class, with 42 susceptibility genes included (p < 0.001, fold enrichment = 1.66, FDR = 1.5%). Among the 42 genes, glutamate receptor genes (GRIA1, GRIK1, GRIK2, GRIN2D, GRIP1, GRM5, GRM7 and SLC1A6) were consistently downregulated across age. We confirmed microarray gene expression changes by the quantitative polymerase chain reaction experiment.

Limitations: Although numerous genes undergo robust changes in expression during the PFC development, some of the changes may be confounded by known
and unknown factors that are intrinsic to the postmortem brain studies.

Conclusions: Multiple schizophrenia susceptibility genes undergo age-dependent expression changes in the human PFC, and any disruption in those genes during the critical period of development may predispose the individuals to schizophrenia.


Submitted Mar. 1, 2009; Revised Jul. 1, 31, 3009; Accepted Jul. 31, 2009.

Acknowledgements: The authors would like to thank Ms. Judy Miller for editing the manuscript and Drs. H. Ronald Zielke and Robert Vigorito of the National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders for their assistance. This work was supported by the Stanley Medical Research Institute and by the Schizophrenia Research Institute, using infrastructure funding from NSW Health, the University of New South Wales School of Psychiatry, and the Prince of Wales Medical Research Institute.

Competing interests: None declared for Drs. Choi and Webster and Ms. Zepp. Dr. Higgs has received consultant fees from the Stanley Medical Research Institute. Dr. Weickert has received speaker fees from AstraZeneca and Astellas and travel assistance from Eli Lilly for work unrelated to this paper.

Contributors: Drs. Choi, Weickert and Webster designed the study. Ms. Zepp acquired the data, which Drs. Choi, Higgs, Weickert and Webster analyzed. Dr. Choi wrote the article. All authors reviewed the article and gave final approval for publication.

Correspondence to: Dr. K.H. Choi, Stanley Medical Research Institute, 9800 Medical Center Dr., Bldg. 2C, Rockville, MD 20850; fax 301 251-8602; choik@stanleyresearch.org