ORIGINAL ARTICLE Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex Carlo Colantuoni Æ Thomas M. Hyde Æ Shruti Mitkus Æ Andrew Joseph Æ Leah Sartorius Æ Claudia Aguirre Æ Johanna Creswell Æ Elizabeth Johnson Æ Amy Deep-Soboslay Æ Mary M. Herman Æ Barbara K. Lipska Æ Daniel R. Weinberger Æ Joel E. Kleinman Received: 23 January 2008 / Accepted: 6 April 2008 / Published online: 10 May 2008 Ó Springer-Verlag 2008 Abstract The molecular basis of complex neuropsychi- atric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizo- phrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann’s area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18–67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes dur- ing the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at http://www.ncbi.nlm.nih.gov/geo/ (accession #: TBA). Keywords Aging Á Disease onset Á Schizophrenia Á Gene expression Á Susceptibility Á Postmortem Á Prefrontal cortex Introduction Strong evidence for a genetic basis of schizophrenia was first provided by the Danish adoption studies (Kety et al. 1976) and was further verified by studies of the relative concordance rates among monozygotic versus dizygotic twin pairs (Cardno and Gottesman 2000; Sullivan et al. 2003). It is assumed that for most individuals with this disorder, the genetic liability for schizophrenia is due to the interaction of risk alleles for multiple genes, rather than a single genetic defect (Gottesman and Shields 1967). Two recent meta-analyses of genome-wide scans have identified multiple loci of particular significance (Badner and Gershon 2002; Lewis et al. 2003). In recent years, a number of genetic polymorphisms have been identified that impact cognition and risk for neuropsychiatric illness. Genes that have been implicated in schizophrenia include catechol-O-methyl transferase (COMT: Li et al. 1996; Kunugi et al. 1997; Li et al. 1999; Egan et al. 2001; Shifman et al. 2002; Chen et al. 2004), neuregulin I (NRG1: Stefansson et al. 2002, 2003; Yang et al. 2003; C. Colantuoni (&) Á T. M. Hyde Á S. Mitkus Á A. Joseph Á L. Sartorius Á C. Aguirre Á J. Creswell Á A. Deep-Soboslay Á M. M. Herman Á B. K. Lipska Á D. R. Weinberger Á J. E. Kleinman Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, IRP, NIMH, NIH, Bethesda, MD 20892, USA e-mail: carlo@illuminatoart.com C. Colantuoni Á E. Johnson Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA C. Colantuoni 713 W. 36th St., Baltimore, MD 21211, USA 123 Brain Struct Funct (2008) 213:255–271 DOI 10.1007/s00429-008-0181-5