Association study of the gamma-aminobutyric acid type a receptor γ2 subunit gene with schizophrenia Clement C. Zai a,b , Arun K. Tiwari a , Nicole King a , Vincenzo De Luca a,c , Daniel J. Mueller a,c , Sajid Shaikh a , Greg W.H. Wong a , Herbert Y. Meltzer d , Jeffrey A. Lieberman e , James L. Kennedy a,b,c, ⁎ a Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8 b Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8 c Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada M5T 1R8 d Psychiatric Hospital at Vanderbilt University, Nashville, Tennessee, USA e New York State Psychiatric Institute, Columbia University Medical Centre, New York City, New York, USA article info abstract Article history: Received 31 March 2009 Received in revised form 11 June 2009 Accepted 10 July 2009 Available online 13 August 2009 Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a strong genetic basis. We analyzed eight GABRG2 and one DRD5 tag single-nucleotide polymorphisms for association with SCZ in 109 small nuclear families and 229 independent SCZ case-control pairs. The marker rs183294 in the 5′ region of GABRG2 was found to be associated with SCZ in both samples with the C allele over-represented in SCZ cases and over-transmitted in SCZ families (combined z = 9.18; p b 1 × 10 -3 ). Taken together, the results of the present study suggest that GABRG2 may be involved in SCZ susceptibility, but further studies are required. © 2009 Elsevier B.V. All rights reserved. Keywords: Schizophrenia GABAA gamma2 subunit gene GABRG2 Dopamine receptor gene DRD5 Genetics Paired case-control sample Family based association test Haplotype analysis 1. Introduction Schizophrenia (SCZ) is a severe debilitating neuropsychia- tric disorder that affects approximately 1% of the general population. Family, twin, and adoption studies support a genetic basis for this disorder (reviewed in McGuffin, 2004), but its etiology is still unclear. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) neurotransmission may underlie the pathophysiology in a subset of SCZ cases (Benes et al., 1992; Delini-Stula and Berdah-Tordjman, 1996; Huntsman et al., 1998; Dean et al., 1999; Wassef et al., 1999; Guidotti et al., 2005). GABA A subunit genes are clustered in the genome, with α1, α6, β2, and γ2 co-located in 5q32–q35 (Johnson et al., 1992; Wilcox et al., 1992; Hicks et al., 1994), a chromosomal region associated with SCZ in a number of genome scans (Sklar et al., 2004; Lewis et al., 2003). Of these subunits, the γ2 regulates benzodiazepines binding to GABA A receptors (Kno- flach et al., 1991; Wafford et al., 1991). The second intracellular loop of the γ2 subunit interacts directly with the carboxyl terminus of the dopamine D 5 receptor, thus providing a direct link between the two neurotransmission systems (Liu et al., 2000). The agonist mediated reciprocal inhibition between the GABA A γ2 subunit and the D 5 receptor via direct physical interaction may underlie the observations of decreased prefrontal cortical D1-like receptor levels (Okubo et al, 1997) and altered GABA A γ2 isoform ratio (Huntsman et al, 1998) in schizophrenia. These alterations could participate in the pathophysiology of schizophrenia (Goldman-Rakic and Selemon, 1997; Moore et al, 1999; Tanaka, 2008) The GABRG2 gene has been associated with prefrontal activity in a study of event-related potentials (Winterer et al., 2000), and febrile seizures (Wallace et al, 2001), a condition linked to a 44% increased risk of SCZ (Vestergaard et al., 2005). Several recent studies reported Schizophrenia Research 114 (2009) 33–38 ⁎ Corresponding author. E-mail address: james_kennedy@camh.net (J.L. Kennedy). 0920-9964/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2009.07.010 Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres