Common Variants in MAGI2 Gene Are Associated with Increased Risk for Cognitive Impairment in Schizophrenic Patients Takayoshi Koide 1,8 , Masahiro Banno 1,8 , Branko Aleksic 1,8 *, Saori Yamashita 1,8 , Tsutomu Kikuchi 1,8 , Kunihiro Kohmura 1,8 , Yasunori Adachi 1,8 , Naoko Kawano 1,8 , Itaru Kushima 1,8 , Yukako Nakamura 1,8 , Takashi Okada 1,8 , Masashi Ikeda 2 , Kazutaka Ohi 3,8 , Yuka Yasuda 3,8 , Ryota Hashimoto 3,4,8 , Toshiya Inada 5 , Hiroshi Ujike 6 , Tetsuya Iidaka 1,8 , Michio Suzuki 7 , Masatoshi Takeda 3,4 , Nakao Iwata 2,8 , Norio Ozaki 1,8 1 Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan, 2 Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan, 3 Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan, 4 Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, and Hamamatsu University Graduate School of Medicine, Osaka, Japan, 5 Department of Psychiatry, Seiwa Hospital, Institute of Neuropsychiatry, Tokyo, Japan, 6 Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan, 7 Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan, 8 CREST, Japan Science and Technology Agency, Tokyo, Japan Abstract Schizophrenia is a complex psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment. MAGI2, a relatively large gene (,1.5 Mbps) that maps to chromosome 7q21, is involved in recruitment of neurotransmitter receptors such as AMPA- and NMDA-type glutamate receptors. A genetic association study designed to evaluate the association between MAGI2 and cognitive performance or schizophrenia has not been conducted. In this case- control study, we examined the relationship of single nucleotide polymorphism (SNP) variations in MAGI2 and risk for schizophrenia in a large Japanese sample and explored the potential relationships between variations in MAGI2 and aspects of human cognitive function related to glutamate activity. Based on the result of first schizophrenia genome-wide association study in a Japanese population (JGWAS), we selected four independent SNPs and performed an association study using a large independent Japanese sample set (cases 1624, controls 1621). Wisconsin Card Sorting Test (WCST) was used to evaluate executive function in 114 cases and 91 controls. We found suggestive evidence for genetic association of common SNPs within MAGI2 locus and schizophrenia in Japanese population. Furthermore in terms of association between MAGI2 and cognitive performance, we observed that genotype effect of rs2190665 on WCST score was significant (p = 0.034) and rs4729938 trended toward significance (p = 0.08). In conclusion, although we could not detect strong genetic evidence for association of common variants in MAGI2 and increased schizophrenia risk in a Japanese population, these SNPs may increase risk of cognitive impairment in schizophrenic patients. Citation: Koide T, Banno M, Aleksic B, Yamashita S, Kikuchi T, et al. (2012) Common Variants in MAGI2 Gene Are Associated with Increased Risk for Cognitive Impairment in Schizophrenic Patients. PLoS ONE 7(5): e36836. doi:10.1371/journal.pone.0036836 Editor: Chuhsing Kate Hsiao, National Taiwan University, Taiwan Received November 20, 2011; Accepted April 7, 2012; Published May 23, 2012 Copyright: ß 2012 Koide et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Funding for this study was provided by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (http://www. mext.go.jp/english/); The Ministry of Health, Labor and Welfare of Japan (http://www.mhlw.go.jp/english/); Grant-in-Aid for ‘‘Integrated research on neuropsychiatric disorder’’ carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan (http://brainprogram.mext.go.jp/); Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Science, Sports and Culture of Japan (https://www.hokatsu-nou.nips.ac.jp/); The Academic Frontier Project for Private Universities, Comparative Cognitive Science Institutes (http://www.meijo-u.ac.jp/sougou/gakujutsu/hitech.html); and the Core Research for Evolutional Science and Technology (http://www.jst.go.jp/kisoken/crest/en/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: branko@med.nagoya-u.ac.jp Introduction Schizophrenia is a complex psychiatric disorder, affecting approximately 1% of the general population. It is characterized by positive symptoms, negative symptoms, and cognitive impairment. The heritability of schizophrenia is estimated to be 64% [1]. Although genes relevant for schizophrenia or variants that may modulate risk for the disease have been identified using both linkage- and candidate-based or whole genome association studies, the genetic basis of schizophrenia is still unclear [2,3,4,5]. Considerable evidence supports a relationship between cogni- tive impairment and functional outcome in schizophrenia [6]. Cognitive impairment is considered a core feature of schizophre- nia that includes problems is processing speed, attention/vigilance, working memory, verbal learning, visual learning, problem solving, and social cognition. The molecular mechanisms respon- sible for cognitive deficits in schizophrenia are to some extent PLoS ONE | www.plosone.org 1 May 2012 | Volume 7 | Issue 5 | e36836